@article{MTMT:35004066, title = {A Perspective on Protein Structure Prediction Using Quantum Computers}, url = {https://m2.mtmt.hu/api/publication/35004066}, author = {Doga, Hakan and Raubenolt, Bryan and Cumbo, Fabio and Joshi, Jayadev and Difilippo, Frank P. and Qin, Jun and Blankenberg, Daniel and Shehab, Omar}, doi = {10.1021/acs.jctc.4c00067}, journal-iso = {J CHEM THEORY COMPUT}, journal = {JOURNAL OF CHEMICAL THEORY AND COMPUTATION}, volume = {20}, unique-id = {35004066}, issn = {1549-9618}, year = {2024}, eissn = {1549-9626}, pages = {3359-3378}, orcid-numbers = {Doga, Hakan/0000-0003-2574-2038; Blankenberg, Daniel/0000-0002-6833-9049} } @article{MTMT:34899603, title = {Experimental and computational approaches for membrane protein insertion and topology determination}, url = {https://m2.mtmt.hu/api/publication/34899603}, author = {Duart, G. and Graña-Montes, R. and Pastor-Cantizano, N. and Mingarro, I.}, doi = {10.1016/j.ymeth.2024.03.012}, journal-iso = {METHODS}, journal = {METHODS}, volume = {226}, unique-id = {34899603}, issn = {1046-2023}, abstract = {Membrane proteins play pivotal roles in a wide array of cellular processes and constitute approximately a quarter of the protein-coding genes across all organisms. Despite their ubiquity and biological significance, our understanding of these proteins remains notably less comprehensive compared to their soluble counterparts. This disparity in knowledge can be attributed, in part, to the inherent challenges associated with employing specialized techniques for the investigation of membrane protein insertion and topology. This review will center on a discussion of molecular biology methodologies and computational prediction tools designed to elucidate the insertion and topology of helical membrane proteins. © 2024 The Authors}, keywords = {Humans; PREDICTIVE VALUE; GENETICS; ARTICLE; FLUORESCENCE; human; ALGORITHM; Chemistry; Membrane Proteins; protein determination; membrane protein; protein localization; TOPOLOGY; enzyme activity; Models, Molecular; calculation; machine learning; protein expression; molecular model; glycosylation; alkaline phosphatase; Molecular Biology; Antibiotic resistance; Hydrophobicity; Computational Biology; translocon; Biotinylation; beta galactosidase; mathematical analysis; protein degradation; Biotin; bioinformatics; bioluminescence resonance energy transfer; Hidden Markov model; procedures; Deep learning; Computational prediction; Experimental approaches; membrane insertion; Helical membrane protein}, year = {2024}, eissn = {1095-9130}, pages = {102-119} } @article{MTMT:34724664, title = {PtdIns4p is required for the autophagosomal recruitment of STX17 (syntaxin 17) to promote lysosomal fusion}, url = {https://m2.mtmt.hu/api/publication/34724664}, author = {Laczkó-Dobos, Hajnalka and Bhattacharjee, Arindam and Maddali, Asha Kiran and Kincses, András and Abuammar, Hussein and Sebőkné Nagy, Krisztina and Páli, Tibor and Dér, András and Hegedűs, Tamás and Csordás, Gábor and Juhász, Gábor}, doi = {10.1080/15548627.2024.2322493}, journal-iso = {AUTOPHAGY}, journal = {AUTOPHAGY}, volume = {20}, unique-id = {34724664}, issn = {1554-8627}, year = {2024}, eissn = {1554-8635}, pages = {1639-1650}, orcid-numbers = {Páli, Tibor/0000-0003-1649-1097; Hegedűs, Tamás/0000-0002-0331-9629; Csordás, Gábor/0000-0001-6871-6839; Juhász, Gábor/0000-0001-8548-8874} } @article{MTMT:35004068, title = {Computational drug development for membrane protein targets}, url = {https://m2.mtmt.hu/api/publication/35004068}, author = {Li, Haijian and Sun, Xiaolin and Cui, Wenqiang and Xu, Marc and Dong, Junlin and Ekundayo, Babatunde Edukpe and Ni, Dongchun and Rao, Zhili and Guo, Liwei and Stahlberg, Henning and Yuan, Shuguang and Vogel, Horst}, doi = {10.1038/s41587-023-01987-2}, journal-iso = {NAT BIOTECHNOL}, journal = {NATURE BIOTECHNOLOGY}, volume = {42}, unique-id = {35004068}, issn = {1087-0156}, year = {2024}, eissn = {1546-1696}, pages = {229-242}, orcid-numbers = {Sun, Xiaolin/0000-0002-1082-2804; Ni, Dongchun/0000-0002-3193-6077; Stahlberg, Henning/0000-0002-1185-4592} } @article{MTMT:35004067, title = {Screening androgen receptor agonists of fish species using machine learning and molecular model in NORMAN water-relevant list}, url = {https://m2.mtmt.hu/api/publication/35004067}, author = {Long, Xiao-Bing and Yao, Chong-Rui and Li, Si-Ying and Zhang, Jin-Ge and Lu, Zhi-Jie and Ma, Dong-Dong and Chen, Chang-Er and Ying, Guang-Guo and Shi, Wen-Jun}, doi = {10.1016/j.jhazmat.2024.133844}, journal-iso = {J HAZARD MATER}, journal = {JOURNAL OF HAZARDOUS MATERIALS}, volume = {468}, unique-id = {35004067}, issn = {0304-3894}, keywords = {fish; machine learning; Molecular docking; AR agonists; NORMAN water-relevant list}, year = {2024}, eissn = {1873-3336}, orcid-numbers = {Chen, Chang-Er/0000-0002-2069-4076} } @article{MTMT:35004065, title = {The S-component fold: a link between bacterial transporters and receptors}, url = {https://m2.mtmt.hu/api/publication/35004065}, author = {Partipilo, Michele and Jan Slotboom, Dirk}, doi = {10.1038/s42003-024-06295-2}, journal-iso = {COMMUN BIOL}, journal = {COMMUNICATIONS BIOLOGY}, volume = {7}, unique-id = {35004065}, year = {2024}, eissn = {2399-3642}, orcid-numbers = {Partipilo, Michele/0000-0003-4150-2341} } @article{MTMT:34544753, title = {Tld1 is a regulator of triglyceride lipolysis that demarcates a lipid droplet subpopulation}, url = {https://m2.mtmt.hu/api/publication/34544753}, author = {Speer, N.O. and Jay, Braun R. and Reynolds, E.G. and Brudnicka, A. and Swanson, J.M.J. and Mike, Henne W.}, doi = {10.1083/jcb.202303026}, journal-iso = {J CELL BIOL}, journal = {JOURNAL OF CELL BIOLOGY}, volume = {223}, unique-id = {34544753}, issn = {0021-9525}, abstract = {Cells store lipids in the form of triglyceride (TG) and sterol ester (SE) in lipid droplets (LDs). Distinct pools of LDs exist, but a pervasive question is how proteins localize to and convey functions to LD subsets. Here, we show that the yeast protein YDR275W/Tld1 (for TG-associated LD protein 1) localizes to a subset of TG-containing LDs and reveal it negatively regulates lipolysis. Mechanistically, Tld1 LD targeting requires TG, and it is mediated by two distinct hydrophobic regions (HRs). Molecular dynamics simulations reveal that Tld1’s HRs interact with TG on LDs and adopt specific conformations on TG-rich LDs versus SE-rich LDs in yeast and human cells. Tld1-deficient yeast display no defect in LD biogenesis but exhibit elevated TG lipolysis dependent on lipase Tgl3. Remarkably, overexpression of Tld1, but not LD protein Pln1/Pet10, promotes TG accumulation without altering SE pools. Finally, we find that Tld1-deficient cells display altered LD mobilization during extended yeast starvation. We propose that Tld1 senses TG-rich LDs and regulates lipolysis on LD subpopulations. © 2023 Speer et al.}, keywords = {Humans; metabolism; GENETICS; ARTICLE; human; protein localization; Saccharomyces cerevisiae; Saccharomyces cerevisiae; nonhuman; regulatory mechanism; Protein Conformation; PROTEIN FUNCTION; human cell; Triglycerides; triacylglycerol; triacylglycerol; unclassified drug; protein expression; protein targeting; Protein Deficiency; LIPASE; amino terminal sequence; molecular dynamics; Hydrophobicity; triacylglycerol lipase; protein interaction; fat droplet; lipolysis; lipolysis; fungal protein; carrier proteins and binding proteins; lipid droplets; Pln1 protein; Tgl3 protein; Tld1 protein}, year = {2024}, eissn = {1540-8140} } @article{MTMT:34879391, title = {Analysis of AlphaMissense data in different protein groups and structural context}, url = {https://m2.mtmt.hu/api/publication/34879391}, author = {Tordai, Hedvig and Torres, O. and Csepi, M. and Padányi, Rita and Lukács, G.L. and Hegedűs, Tamás}, doi = {10.1038/s41597-024-03327-8}, journal-iso = {SCI DATA}, journal = {SCIENTIFIC DATA}, volume = {11}, unique-id = {34879391}, year = {2024}, eissn = {2052-4463}, orcid-numbers = {Tordai, Hedvig/0000-0002-0875-5569; Padányi, Rita/0000-0001-7798-0463; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:33769110, title = {Scalable Inhibitors of the Nsp3-Nsp4 Coupling in SARS-CoV-2}, url = {https://m2.mtmt.hu/api/publication/33769110}, author = {Azizogli, A.-R. and Pai, V. and Coppola, F. and Jafari, R. and Dodd-O, J.B. and Harish, R. and Balasubramanian, B. and Kashyap, J. and Acevedo-Jake, A.M. and Král, P. and Kumar, V.A.}, doi = {10.1021/acsomega.2c06384}, journal-iso = {ACS OMEGA}, journal = {ACS OMEGA}, volume = {8}, unique-id = {33769110}, issn = {2470-1343}, abstract = {The human Betacoronavirus SARS-CoV-2 is a novel pathogen claiming millions of lives and causing a global pandemic that has disrupted international healthcare systems, economies, and communities. The virus is fast mutating and presenting more infectious but less lethal versions. Currently, some small-molecule therapeutics have received FDA emergency use authorization for the treatment of COVID-19, including Lagevrio (molnupiravir) and Paxlovid (nirmaltrevir/ritonavir), which target the RNA-dependent RNA polymerase and the 3CLpro main protease, respectively. Proteins downstream in the viral replication process, specifically the nonstructural proteins (Nsps1-16), are potential drug targets due to their crucial functions. Of these Nsps, Nsp4 is a particularly promising drug target due to its involvement in the SARS-CoV viral replication and double-membrane vesicle formation (mediated via interaction with Nsp3). Given the degree of sequence conservation of these two Nsps across the Betacoronavirus clade, their protein-protein interactions and functions are likely to be conserved as well in SARS-CoV-2. Through AlphaFold2 and its recent advancements, protein structures were generated of Nsp3 and 4 lumenal loops of interest. Then, using a combination of molecular docking suites and an existing library of lead-like compounds, we virtually screened 7 million ligands to identify five putative ligand inhibitors of Nsp4, which could present an alternative pharmaceutical approach against SARS-CoV-2. These ligands exhibit promising lead-like properties (ideal molecular weight and log P profiles), maintain fixed-Nsp4-ligand complexes in molecular dynamics (MD) simulations, and tightly associate with Nsp4 via hydrophobic interactions. Additionally, alternative peptide inhibitors based on Nsp3 were designed and shown in MD simulations to provide a highly stable binding to the Nsp4 protein. Finally, these therapeutics were attached to dendrimer structures to promote their multivalent binding with Nsp4, especially its large flexible luminal loop (Nsp4LLL). The therapeutics tested in this study represent many different approaches for targeting large flexible protein structures, especially those localized to the ER. This study is the first work targeting the membrane rearrangement system of viruses and will serve as a potential avenue for treating viruses with similar replicative function. © 2023 The Authors. Published by American Chemical Society.}, year = {2023}, eissn = {2470-1343}, pages = {5349-5360} } @article{MTMT:34360222, title = {Viroporins of Mpox Virus}, url = {https://m2.mtmt.hu/api/publication/34360222}, author = {Basu, Kingshuk and Krugliak, Miriam and Arkin, Isaiah T.}, doi = {10.3390/ijms241813828}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34360222}, issn = {1661-6596}, abstract = {Mpox or monkeypox virus (MPXV) belongs to the subclass of Poxviridae and has emerged recently as a global threat. With a limited number of anti-viral drugs available for this new virus species, it is challenging to thwart the illness it begets. Therefore, characterizing new drug targets in the virus may prove advantageous to curbing the disease. Since channels as a family are excellent drug targets, we have sought to identify viral ion channels for this virus, which are instrumental in formulating channel-blocking anti-viral drugs. Bioinformatics analyses yielded eight transmembranous proteins smaller or equal to 100 amino acids in length. Subsequently, three independent bacteria-based assays have pointed to five of the eight proteins that exhibit ion channel activity. Finally, we propose a tentative structure of four ion channels from their primary amino acid sequences, employing AlphaFold2 and molecular dynamic simulation methods. These results may represent the first steps in characterizing MPXV viroporins en route to developing blockers that inhibit their function.}, keywords = {Molecular dynamic simulation; mpox virus; viral ion channels; ion channel assay}, year = {2023}, eissn = {1422-0067} } @article{MTMT:33822289, title = {An agnostic analysis of the human AlphaFold2 proteome using local protein conformations}, url = {https://m2.mtmt.hu/api/publication/33822289}, author = {de Brevern, A.G.}, doi = {10.1016/j.biochi.2022.11.009}, journal-iso = {BIOCHIMIE}, journal = {BIOCHIMIE}, volume = {207}, unique-id = {33822289}, issn = {0300-9084}, year = {2023}, eissn = {1638-6183}, pages = {11-19} } @article{MTMT:34662619, title = {Unique Properties of Nutrient Channels on Plasmodium-Infected Erythrocytes}, url = {https://m2.mtmt.hu/api/publication/34662619}, author = {Desai, Sanjay Arvind}, doi = {10.3390/pathogens12101211}, journal-iso = {PATHOGENS}, journal = {PATHOGENS}, volume = {12}, unique-id = {34662619}, keywords = {SELECTIVITY; PERMEATION; nutrient uptake; ion channel; CONDUCTANCE; Malaria; antimalarial drug discovery}, year = {2023}, eissn = {2076-0817} } @article{MTMT:33769108, title = {Secondary and Topological Structural Merge Prediction of Alpha-Helical Transmembrane Proteins Using a Hybrid Model Based on Hidden Markov and Long Short-Term Memory Neural Networks}, url = {https://m2.mtmt.hu/api/publication/33769108}, author = {Gao, T. and Zhao, Y. and Zhang, L. and Wang, H.}, doi = {10.3390/ijms24065720}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {33769108}, issn = {1661-6596}, abstract = {Alpha-helical transmembrane proteins (αTMPs) play essential roles in drug targeting and disease treatments. Due to the challenges of using experimental methods to determine their structure, αTMPs have far fewer known structures than soluble proteins. The topology of transmembrane proteins (TMPs) can determine the spatial conformation relative to the membrane, while the secondary structure helps to identify their functional domain. They are highly correlated on αTMPs sequences, and achieving a merge prediction is instructive for further understanding the structure and function of αTMPs. In this study, we implemented a hybrid model combining Deep Learning Neural Networks (DNNs) with a Class Hidden Markov Model (CHMM), namely HDNNtopss. DNNs extract rich contextual features through stacked attention-enhanced Bidirectional Long Short-Term Memory (BiLSTM) networks and Convolutional Neural Networks (CNNs), and CHMM captures state-associative temporal features. The hybrid model not only reasonably considers the probability of the state path but also has a fitting and feature-extraction capability for deep learning, which enables flexible prediction and makes the resulting sequence more biologically meaningful. It outperforms current advanced merge-prediction methods with a Q4 of 0.779 and an MCC of 0.673 on the independent test dataset, which have practical, solid significance. In comparison to advanced prediction methods for topological and secondary structures, it achieves the highest topology prediction with a Q2 of 0.884, which has a strong comprehensive performance. At the same time, we implemented a joint training method, Co-HDNNtopss, and achieved a good performance to provide an important reference for similar hybrid-model training. © 2023 by the authors.}, keywords = {SECONDARY STRUCTURE; PROTEIN SECONDARY STRUCTURE; ALGORITHM; Chemistry; Algorithms; Membrane Proteins; membrane protein; Protein Structure, Secondary; Memory, Short-Term; short term memory; transmembrane protein; topology structure; Neural Networks, Computer; class hidden markov model (CHMM); deep learning neural networks (DNNs); long short-term memory (LSTM) networks; merge prediction}, year = {2023}, eissn = {1422-0067} } @article{MTMT:34360224, title = {Template-free prediction of a new monotopic membrane protein fold and assembly by AlphaFold2}, url = {https://m2.mtmt.hu/api/publication/34360224}, author = {Gulsevin, Alican and Han, Bing and Porta, Jason C. and Mchaourab, Hassane S. and Meiler, Jens and Kenworthy, Anne K.}, doi = {10.1016/j.bpj.2022.11.011}, journal-iso = {BIOPHYS J}, journal = {BIOPHYSICAL JOURNAL}, volume = {122}, unique-id = {34360224}, issn = {0006-3495}, abstract = {AlphaFold2 (AF2) has revolutionized the field of protein structural prediction. Here, we test its ability to predict the tertiary and quaternary structure of a previously undescribed scaffold with new folds and unusual architecture, the monotopic membrane protein caveolin-1 (CAV1). CAV1 assembles into a disc-shaped oligomer composed of 11 symmetrically arranged protomers, each assuming an identical new fold, and contains the largest parallel 5-barrel known to exist in nature. Remarkably, AF2 predicts both the fold of the protomers and the interfaces between them. It also assembles between seven and 15 copies of CAV1 into disc-shaped complexes. However, the predicted multimers are energetically strained, especially the parallel 5-barrel. These findings highlight the ability of AF2 to correctly predict new protein folds and oligomeric assemblies at a granular level while missing some elements of higher-order complexes, thus positing a new direction for the continued development of deep-learning protein structure prediction approaches.}, year = {2023}, eissn = {1542-0086}, pages = {2041-2052} } @article{MTMT:34360227, title = {Mammalian lipid droplets: structural, pathological, immunological and anti-toxicological roles}, url = {https://m2.mtmt.hu/api/publication/34360227}, author = {Hammoudeh, Nour and Soukkarieh, Chadi and Murphy, Denis J. and Hanano, Abdulsamie}, doi = {10.1016/j.plipres.2023.101233}, journal-iso = {PROG LIPID RES}, journal = {PROGRESS IN LIPID RESEARCH}, volume = {91}, unique-id = {34360227}, issn = {0163-7827}, abstract = {Mammalian lipid droplets (LDs) are specialized cytosolic organelles consisting of a neutral lipid core surrounded by a membrane made up of a phospholipid monolayer and a specific population of proteins that varies according to the location and function of each LD. Over the past decade, there have been significant advances in the understanding of LD biogenesis and functions. LDs are now recognized as dynamic organelles that participate in many aspects of cellular homeostasis plus other vital functions. LD biogenesis is a complex, highly-regulated process with assembly occurring on the endoplasmic reticulum although aspects of the underpinning molecular mechanisms remain elusive. For example, it is unclear how many enzymes participate in the biosynthesis of the neutral lipid components of LDs and how this process is coordinated in response to different metabolic cues to promote or suppress LD formation and turnover. In addition to enzymes involved in the biosynthesis of neutral lipids, various scaffolding proteins play roles in coordinating LD formation. Despite their lack of ultrastructural diversity, LDs in different mammalian cell types are involved in a wide range of biological functions. These include roles in membrane homeostasis, regulation of hypoxia, neoplastic in-flammatory responses, cellular oxidative status, lipid peroxidation, and protection against potentially toxic intracellular fatty acids and lipophilic xenobiotics. Herein, the roles of mammalian LDs and their associated proteins are reviewed with a particular focus on their roles in pathological, immunological and anti-toxicological processes.}, year = {2023}, eissn = {1873-2194} } @article{MTMT:34401705, title = {How AlphaFold2 shaped the structural coverage of the human transmembrane proteome}, url = {https://m2.mtmt.hu/api/publication/34401705}, author = {Jambrich, M.A. and Tusnády, Gábor and Dobson, László}, doi = {10.1038/s41598-023-47204-7}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {13}, unique-id = {34401705}, issn = {2045-2322}, abstract = {AlphaFold2 (AF2) provides a 3D structure for every known or predicted protein, opening up new prospects for virtually every field in structural biology. However, working with transmembrane protein molecules pose a notorious challenge for scientists, resulting in a limited number of experimentally determined structures. Consequently, algorithms trained on this finite training set also face difficulties. To address this issue, we recently launched the TmAlphaFold database, where predicted AlphaFold2 structures are embedded into the membrane plane and a quality assessment (plausibility of the membrane-embedded structure) is provided for each prediction using geometrical evaluation. In this paper, we analyze how AF2 has improved the structural coverage of membrane proteins compared to earlier years when only experimental structures were available, and high-throughput structure prediction was greatly limited. We also evaluate how AF2 can be used to search for (distant) homologs in highly diverse protein families. By combining quality assessment and homology search, we can pinpoint protein families where AF2 accuracy is still limited, and experimental structure determination would be desirable. © 2023, The Author(s).}, year = {2023}, eissn = {2045-2322} } @article{MTMT:34360225, title = {Impact of E484Q and L452R Mutations on Structure and Binding Behavior of SARS-CoV-2 B.1.617.1 Using Deep Learning AlphaFold2, Molecular Docking and Dynamics Simulation}, url = {https://m2.mtmt.hu/api/publication/34360225}, author = {Jiao, Yanqi and Xing, Yichen and Sun, Yao}, doi = {10.3390/ijms241411564}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34360225}, issn = {1661-6596}, abstract = {During the outbreak of COVID-19, many SARS-CoV-2 variants presented key amino acid mutations that influenced their binding abilities with angiotensin-converting enzyme 2 (hACE2) and neutralizing antibodies. For the B.1.617 lineage, there had been fears that two key mutations, i.e., L452R and E484Q, would have additive effects on the evasion of neutralizing antibodies. In this paper, we systematically investigated the impact of the L452R and E484Q mutations on the structure and binding behavior of B.1.617.1 using deep learning AlphaFold2, molecular docking and dynamics simulation. We firstly predicted and verified the structure of the S protein containing L452R and E484Q mutations via the AlphaFold2-calculated pLDDT value and compared it with the experimental structure. Next, a molecular simulation was performed to reveal the structural and interaction stabilities of the S protein of the double mutant variant with hACE2. We found that the double mutations, L452R and E484Q, could lead to a decrease in hydrogen bonds and higher interaction energy between the S protein and hACE2, demonstrating the lower structural stability and the worse binding affinity in the long dynamic evolutional process, even though the molecular docking showed the lower binding energy score of the S1 RBD of the double mutant variant with hACE2 than that of the wild type (WT) with hACE2. In addition, docking to three approved neutralizing monoclonal antibodies (mAbs) showed a reduced binding affinity of the double mutant variant, suggesting a lower neutralization ability of the mAbs against the double mutant variant. Our study helps lay the foundation for further SARS-CoV-2 studies and provides bioinformatics and computational insights into how the double mutations lead to immune evasion, which could offer guidance for subsequent biomedical studies.}, keywords = {Molecular docking; Molecular Dynamics Simulation; AlphaFold2; double mutant variant}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Sun, Yao/0000-0001-8802-0580} } @article{MTMT:34393503, title = {Co-evolution at protein–protein interfaces guides inference of stoichiometry of oligomeric protein complexes by de novo structure prediction}, url = {https://m2.mtmt.hu/api/publication/34393503}, author = {Kilian, M. and Bischofs, I.B.}, doi = {10.1111/mmi.15169}, journal-iso = {MOL MICROBIOL}, journal = {MOLECULAR MICROBIOLOGY}, volume = {120}, unique-id = {34393503}, issn = {0950-382X}, year = {2023}, eissn = {1365-2958}, pages = {763-782} } @article{MTMT:33822284, title = {Itch receptor MRGPRX4 interacts with the receptor activity–modifying proteins}, url = {https://m2.mtmt.hu/api/publication/33822284}, author = {Kotliar, I.B. and Ceraudo, E. and Kemelmakher-Liben, K. and Oren, D.A. and Lorenzen, E. and Dodig-Crnković, T. and Horioka-Duplix, M. and Huber, T. and Schwenk, J.M. and Sakmar, T.P.}, doi = {10.1016/j.jbc.2023.104664}, journal-iso = {J BIOL CHEM}, journal = {JOURNAL OF BIOLOGICAL CHEMISTRY}, volume = {299}, unique-id = {33822284}, issn = {0021-9258}, year = {2023}, eissn = {1083-351X} } @article{MTMT:33786659, title = {The intrinsically disordered protein glue of the myelin major dense line: Linking AlphaFold2 predictions to experimental data}, url = {https://m2.mtmt.hu/api/publication/33786659}, author = {Krokengen, O.C. and Raasakka, A. and Kursula, P.}, doi = {10.1016/j.bbrep.2023.101474}, journal-iso = {BIOCHEM BIOPHYS REP}, journal = {BIOCHEMISTRY AND BIOPHYSICS REPORTS}, volume = {34}, unique-id = {33786659}, issn = {2405-5808}, year = {2023}, eissn = {2405-5808} } @article{MTMT:33822300, title = {Characterization of the renal tubular transport of creatinine by activity-based protein profiling and transport kinetics}, url = {https://m2.mtmt.hu/api/publication/33822300}, author = {Ma, Y. and Zhang, M. and Yang, J. and Zhu, L. and Dai, J. and Wu, X.}, doi = {10.1016/j.ejps.2022.106342}, journal-iso = {EUR J PHARM SCI}, journal = {EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES}, volume = {180}, unique-id = {33822300}, issn = {0928-0987}, year = {2023}, eissn = {1879-0720} } @article{MTMT:33822298, title = {Metastable alpha-rich and beta-rich conformations of small Aβ42 peptide oligomers}, url = {https://m2.mtmt.hu/api/publication/33822298}, author = {Nguyen, P.H. and Sterpone, F. and Derreumaux, P.}, doi = {10.1002/prot.26495}, journal-iso = {PROTEINS}, journal = {PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS}, unique-id = {33822298}, issn = {0887-3585}, year = {2023}, eissn = {1097-0134} } @article{MTMT:33781536, title = {Restriction of access to the central cavity is a major contributor to substrate selectivity in plant ABCG transporters}, url = {https://m2.mtmt.hu/api/publication/33781536}, author = {Pakuła, K. and Sequeiros-Borja, C. and Biała-Leonhard, W. and Pawela, A. and Banasiak, J. and Bailly, A. and Radom, M. and Geisler, M. and Brezovsky, J. and Jasiński, M.}, doi = {10.1007/s00018-023-04751-6}, journal-iso = {CELL MOL LIFE SCI}, journal = {CELLULAR AND MOLECULAR LIFE SCIENCES}, volume = {80}, unique-id = {33781536}, issn = {1420-682X}, abstract = {ABCG46 of the legume Medicago truncatula is an ABC-type transporter responsible for highly selective translocation of the phenylpropanoids, 4-coumarate, and liquiritigenin, over the plasma membrane. To investigate molecular determinants of the observed substrate selectivity, we applied a combination of phylogenetic and biochemical analyses, AlphaFold2 structure prediction, molecular dynamics simulations, and mutagenesis. We discovered an unusually narrow transient access path to the central cavity of MtABCG46 that constitutes an initial filter responsible for the selective translocation of phenylpropanoids through a lipid bilayer. Furthermore, we identified remote residue F562 as pivotal for maintaining the stability of this filter. The determination of individual amino acids that impact the selective transport of specialized metabolites may provide new opportunities associated with ABCGs being of interest, in many biological scenarios. © 2023, The Author(s).}, keywords = {SELECTIVITY; metabolism; GENETICS; PHYLOGENY; PHYLOGENY; MUTAGENESIS; MUTAGENESIS; ATP-Binding Cassette Transporters; molecular dynamics; ABC transporter; Phenylpropanoids; ABC TRANSPORTERS; Molecular Dynamics Simulation; ATP Binding Cassette Transporter, Subfamily G; AlphaFold2; Access path}, year = {2023}, eissn = {1420-9071} } @article{MTMT:34598991, title = {Selective Activation of a TRPC6 Ion Channel Over TRPC3 by Metalated Type-B Polycyclic Polyprenylated Acylphloroglucinols}, url = {https://m2.mtmt.hu/api/publication/34598991}, author = {Peslalz, Philipp and Kraus, Frank and Izzo, Flavia and Bleisch, Anton and El Hamdaoui, Yamina and Schulz, Ina and Kany, Andreas M. and Hirsch, Anna K. H. and Friedland, Kristina and Plietker, Bernd}, doi = {10.1021/acs.jmedchem.3c01170}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {66}, unique-id = {34598991}, issn = {0022-2623}, abstract = {Selective modulation of TRPC6 ion channels is a promising therapeutic approach for neurodegenerative diseases and depression. A significant advancement showcases the selective activation of TRPC6 through metalated type-B PPAP, termed PPAP53. This success stems from PPAP53's 1,3-diketone motif facilitating metal coordination. PPAP53 is water-soluble and as potent as hyperforin, the gold standard in this field. In contrast to type-A, type-B PPAPs offer advantages such as gram-scale synthesis, easy derivatization, and long-term stability. Our investigations reveal PPAP53 selectively binding to the C-terminus of TRPC6. Although cryoelectron microscopy has resolved the majority of the TRPC6 structure, the binding site in the C-terminus remained unresolved. To address this issue, we employed state-of-the-art artificial-intelligence-based protein structure prediction algorithms to predict the missing region. Our computational results, validated against experimental data, indicate that PPAP53 binds to the (LLKL780)-L-777-region of the C-terminus, thus providing critical insights into the binding mechanism of PPAP53.}, year = {2023}, eissn = {1520-4804}, pages = {15061-15072}, orcid-numbers = {Peslalz, Philipp/0000-0002-7427-5352; Plietker, Bernd/0000-0001-8423-6173} } @article{MTMT:34662617, title = {Structural Modeling of Cytokine-Receptor-JAK2 Signaling Complexes Using AlphaFold Multimer}, url = {https://m2.mtmt.hu/api/publication/34662617}, author = {Pogozheva, Irina D. and Cherepanov, Stanislav and Park, Sang-Jun and Raghavan, Malini and Im, Wonpil and Lomize, Andrei L.}, doi = {10.1021/acs.jcim.3c00926}, journal-iso = {J CHEM INF MODEL}, journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING}, volume = {63}, unique-id = {34662617}, issn = {1549-9596}, year = {2023}, eissn = {1549-960X}, pages = {5874-5895}, orcid-numbers = {Cherepanov, Stanislav/0000-0001-9459-1849; Park, Sang-Jun/0000-0002-7307-3724; Raghavan, Malini/0000-0002-1345-9318} } @article{MTMT:34662620, title = {AlphaFold developers Demis Hassabis and John Jumper share the 2023 Albert Lasker Basic Medical Research Award}, url = {https://m2.mtmt.hu/api/publication/34662620}, author = {Sosnick, Tobin R.}, doi = {10.1172/JCI174915}, journal-iso = {J CLIN INVEST}, journal = {JOURNAL OF CLINICAL INVESTIGATION}, volume = {133}, unique-id = {34662620}, issn = {0021-9738}, year = {2023}, eissn = {1558-8238} } @article{MTMT:33656509, title = {Machine learning in computational modelling of membrane protein sequences and structures: From methodologies to applications}, url = {https://m2.mtmt.hu/api/publication/33656509}, author = {Sun, J. and Kulandaisamy, A. and Liu, J. and Hu, K. and Gromiha, M.M. and Zhang, Y.}, doi = {10.1016/j.csbj.2023.01.036}, journal-iso = {CSBJ}, journal = {COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL}, volume = {21}, unique-id = {33656509}, issn = {2001-0370}, year = {2023}, eissn = {2001-0370}, pages = {1205-1226} } @article{MTMT:34165783, title = {TMKit: a Python interface for computational analysis of transmembrane proteins}, url = {https://m2.mtmt.hu/api/publication/34165783}, author = {Sun, Jianfeng and Kulandaisamy, Arulsamy and Ru, Jinlong and Gromiha, M. Michael and Cribbs, Adam P.}, doi = {10.1093/bib/bbad288}, journal-iso = {BRIEF BIOINFORM}, journal = {BRIEFINGS IN BIOINFORMATICS}, volume = {24}, unique-id = {34165783}, issn = {1467-5463}, year = {2023}, eissn = {1477-4054}, orcid-numbers = {Cribbs, Adam P./0000-0001-5288-3077} } @article{MTMT:34109785, title = {AlphaCutter: Efficient removal of non-globular regions from predicted protein structures}, url = {https://m2.mtmt.hu/api/publication/34109785}, author = {Tam, C. and Iwasaki, W.}, doi = {10.1002/pmic.202300176}, journal-iso = {PROTEOMICS}, journal = {PROTEOMICS}, volume = {23}, unique-id = {34109785}, issn = {1615-9853}, abstract = {A huge number of high-quality predicted protein structures are now publicly available. However, many of these structures contain non-globular regions, which diminish the performance of downstream structural bioinformatic applications. In this study, we develop AlphaCutter for the removal of non-globular regions from predicted protein structures. A large-scale cleaning of 542,380 predicted SwissProt structures highlights that AlphaCutter is able to (1) remove non-globular regions that are undetectable using pLDDT scores and (2) preserve high integrity of the cleaned domain regions. As useful applications, AlphaCutter improved the folding energy scores and sequence recovery rates in the re-design of domain regions. On average, AlphaCutter takes less than 3 s to clean a protein structure, enabling efficient cleaning of the exploding number of predicted protein structures. AlphaCutter is available at https://github.com/johnnytam100/AlphaCutter. AlphaCutter-cleaned SwissProt structures are available for download at https://doi.org/10.5281/zenodo.7944483. © 2023 The Authors. Proteomics published by Wiley-VCH GmbH.}, keywords = {ARTICLE; protein structure; cleaning; Swiss-Prot; AlphaFold; non-globular regions; protein structure validation}, year = {2023}, eissn = {1615-9861} } @article{MTMT:33616237, title = {The LIV-1 Subfamily of Zinc Transporters: From Origins to Present Day Discoveries}, url = {https://m2.mtmt.hu/api/publication/33616237}, author = {Taylor, K.M.}, doi = {10.3390/ijms24021255}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {33616237}, issn = {1661-6596}, abstract = {This review explains the origin of the LIV-1 family of zinc transporters, paying attention to how this family of nine human proteins was originally discovered. Structural and functional differences between these nine human LIV-1 family members and the five other ZIP transporters are examined. These differences are both related to aspects of the protein sequence, the conservation of important motifs and to the effect this may have on their overall function. The LIV-1 family are dependent on various post-translational modifications, such as phosphorylation and cleavage, which play an important role in their ability to transport zinc. These modifications and their implications are discussed in detail. Some of these proteins have been implicated in cancer which is examined. Furthermore, some additional areas of potential fruitful discovery are discussed and suggested as worthy of examination in the future. © 2023 by the author.}, keywords = {Humans; metabolism; human; amino acid sequence; amino acid sequence; ZINC; ZINC; Membrane Transport Proteins; carrier protein; Carrier Proteins; zinc-binding protein; LIV-1; ZIP7; Zinc transport; SLC39A; Zip6; LIV1; LIV-1 family; ZIP10}, year = {2023}, eissn = {1422-0067} } @article{MTMT:33822294, title = {Deorphanizing Peptides Using Structure Prediction}, url = {https://m2.mtmt.hu/api/publication/33822294}, author = {Teufel, F. and Refsgaard, J.C. and Kasimova, M.A. and Deibler, K. and Madsen, C.T. and Stahlhut, C. and Grønborg, M. and Winther, O. and Madsen, D.}, doi = {10.1021/acs.jcim.3c00378}, journal-iso = {J CHEM INF MODEL}, journal = {JOURNAL OF CHEMICAL INFORMATION AND MODELING}, unique-id = {33822294}, issn = {1549-9596}, year = {2023}, eissn = {1549-960X} } @article{MTMT:34360223, title = {Spf1 and Ste24: quality controllers of transmembrane protein topology in the eukaryotic cell}, url = {https://m2.mtmt.hu/api/publication/34360223}, author = {Tipper, Donald J. and Harley, Carol A.}, doi = {10.3389/fcell.2023.1220441}, journal-iso = {FRONT CELL DEV BIOL}, journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, volume = {11}, unique-id = {34360223}, issn = {2296-634X}, abstract = {DNA replication, transcription, and translation in eukaryotic cells occur with decreasing but still high fidelity. In contrast, for the estimated 33% of the human proteome that is inserted as transmembrane (TM) proteins, insertion with a non-functional inverted topology is frequent. Correct topology is essential for function and trafficking to appropriate cellular compartments and is controlled principally by responses to charged residues within 15 residues of the inserted TM domain (TMD); the flank with the higher positive charge remains in the cytosol (inside), following the positive inside rule (PIR). Yeast (Saccharomyces cerevisiae) mutants that increase insertion contrary to the PIR were selected. Mutants with strong phenotypes were found only in SPF1 and STE24 (human cell orthologs are ATP13A1 and ZMPSte24) with, at the time, no known relevant functions. Spf1/Atp13A1 is now known to dislocate to the cytosol TM proteins inserted contrary to the PIR, allowing energy-conserving reinsertion. We hypothesize that Spf1 and Ste24 both recognize the short, positively charged ER luminal peptides of TM proteins inserted contrary to the PIR, accepting these peptides into their large membrane-spanning, water-filled cavities through interaction with their many interior surface negative charges. While entry was demonstrated for Spf1, no published evidence directly demonstrates substrate entry to the Ste24 cavity, internal access to its zinc metalloprotease (ZMP) site, or active withdrawal of fragments, which may be essential for function. Spf1 and Ste24 comprise a PIR quality control system that is conserved in all eukaryotes and presumably evolved in prokaryotic progenitors as they gained differentiated membrane functions. About 75% of the PIR is imposed by this quality control system, which joins the UPR, ERAD, and autophagy (ER-phagy) in coordinated, overlapping quality control of ER protein function.}, keywords = {TOPOLOGY; quality control; Transmembrane proteins; positive inside rule; topology error recognition}, year = {2023}, eissn = {2296-634X} } @article{MTMT:34360226, title = {Outer membrane β-barrel structure prediction through the lens of AlphaFold2}, url = {https://m2.mtmt.hu/api/publication/34360226}, author = {Topitsch, Annika and Schwede, Torsten and Pereira, Joana}, doi = {10.1002/prot.26552}, journal-iso = {PROTEINS}, journal = {PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS}, unique-id = {34360226}, issn = {0887-3585}, abstract = {Most proteins found in the outer membrane of gram-negative bacteria share a common domain: the transmembrane & beta;-barrel. These outer membrane & beta;-barrels (OMBBs) occur in multiple sizes and different families with a wide range of functions evolved independently by amplification from a pool of homologous ancestral & beta;& beta;-hairpins. This is part of the reason why predicting their three-dimensional (3D) structure, especially by homology modeling, is a major challenge. Recently, DeepMind's AlphaFold v2 (AF2) became the first structure prediction method to reach close-to-experimental atomic accuracy in CASP even for difficult targets. However, membrane proteins, especially OMBBs, were not abundant during their training, raising the question of how accurate the predictions are for these families. In this study, we assessed the performance of AF2 in the prediction of OMBBs and OMBB-like folds of various topologies using an in-house-developed tool for the analysis of OMBB 3D structures, and barrOs. In agreement with previous studies on other membrane protein classes, our results indicate that AF2 predicts transmembrane & beta;-barrel structures at high accuracy independently of the use of templates, even for novel topologies absent from the training set. These results provide confidence on the models generated by AF2 and open the door to the structural elucidation of novel transmembrane & beta;-barrel topologies identified in high-throughput OMBB annotation studies or designed de novo.}, keywords = {PROTEIN; MODELS; Protein Folding; Protein Conformation; Databases; Computational Biology; Bacterial Outer Membrane Proteins; Molecular; beta-strand}, year = {2023}, eissn = {1097-0134} } @article{MTMT:34662618, title = {Channel Formation in Cry Toxins: An Alphafold-2 Perspective}, url = {https://m2.mtmt.hu/api/publication/34662618}, author = {Torres, Jaume and Surya, Wahyu and Boonserm, Panadda}, doi = {10.3390/ijms242316809}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34662618}, issn = {1661-6596}, keywords = {pore formation; AlphaFold; Cry toxins}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Torres, Jaume/0000-0002-1282-9727; Surya, Wahyu/0000-0001-9240-371X; Boonserm, Panadda/0000-0002-2057-3944} } @article{MTMT:33674804, title = {The opportunities and challenges posed by the new generation of deep learning-based protein structure predictors}, url = {https://m2.mtmt.hu/api/publication/33674804}, author = {Varadi, M. and Bordin, N. and Orengo, C. and Velankar, S.}, doi = {10.1016/j.sbi.2023.102543}, journal-iso = {CURR OPIN STRUC BIOL}, journal = {CURRENT OPINION IN STRUCTURAL BIOLOGY}, volume = {79}, unique-id = {33674804}, issn = {0959-440X}, year = {2023}, eissn = {1879-033X} } @article{MTMT:33822290, title = {Structures of Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT) Isoforms and Their Interactions with Chloroquine}, url = {https://m2.mtmt.hu/api/publication/33822290}, author = {Willems, A. and Kalaw, A. and Ecer, A. and Kotwal, A. and Roepe, L.D. and Roepe, P.D.}, doi = {10.1021/acs.biochem.2c00669}, journal-iso = {BIOCHEMISTRY-US}, journal = {BIOCHEMISTRY}, volume = {62}, unique-id = {33822290}, issn = {0006-2960}, year = {2023}, eissn = {1520-4995}, pages = {1093-1110} } @article{MTMT:34132570, title = {Fungal carboxylate transporters: recent manipulations and applications}, url = {https://m2.mtmt.hu/api/publication/34132570}, author = {Wu, Taju and Li, Jingen and Tian, Chaoguang}, doi = {10.1007/s00253-023-12720-z}, journal-iso = {APPL MICROBIOL BIOT}, journal = {APPLIED MICROBIOLOGY AND BIOTECHNOLOGY}, unique-id = {34132570}, issn = {0175-7598}, abstract = {Carboxylic acids containing acidic groups with additional keto/hydroxyl-groups or unsaturated bond have displayed great applicability in the food, agricultural, cosmetic, textile, and pharmaceutical industries. The traditional approach for carboxylate production through chemical synthesis is based on petroleum derivatives, resulting in concerns for the environmental complication and energy crisis, and increasing attention has been attracted to the eco-friendly and renewable bio-based synthesis for carboxylate production. The efficient and specific export of target carboxylic acids through the microbial membrane is essential for high productivity, yield, and titer of bio-based carboxylates. Therefore, understanding the characteristics, regulations, and efflux mechanisms of carboxylate transporters will efficiently increase industrial biotechnological production of carboxylic acids. Several transporters from fungi have been reported and used for improved synthesis of target products. The transport activity and substrate specificity are two key issues that need further improvement in the application of carboxylate transporters. This review presents developments in the structural and functional diversity of carboxylate transporters, focusing on the modification and regulation of carboxylate transporters to alter the transport activity and substrate specificity, providing new strategy for transporter engineering in constructing microbial cell factory for carboxylate production.}, keywords = {PROTEIN; IDENTIFICATION; PATHWAY; Fungi; SACCHAROMYCES-CEREVISIAE; TRANSPORTER; CITRATE; protein modification; carboxylic acid; Accurate prediction; ASPERGILLUS-ORYZAE; FUMARIC-ACID PRODUCTION; TORULOPSIS-GLABRATA}, year = {2023}, eissn = {1432-0614} } @article{MTMT:33971028, title = {Virtual screening and activity evaluation of human uric acid transporter 1 (hURAT1) inhibitors}, url = {https://m2.mtmt.hu/api/publication/33971028}, author = {Yang, Yacong and Hu, Yu and Yao, Fengli and Yang, Jinbo and Ge, Leilei and Wang, Peng and Xu, Ximing}, doi = {10.1039/d2ra07193b}, journal-iso = {RSC ADV}, journal = {RSC ADVANCES}, volume = {13}, unique-id = {33971028}, issn = {2046-2069}, abstract = {Hyperuricemia is a disease caused by disorder of purine metabolism, mainly due to insufficient renal excretion of uric acid. Urate transporter 1 (URAT1) is the most widely studied target of urate transporters, and used for uric acid (UA) reabsorption. This study used the AlphaFold2 algorithm to predict the structure of URAT1. Virtual screening and biological evaluation were used to discover novel URAT1 inhibitors that target the critical amino acids. Seven compounds were screened from the T2220 database and validated as URAT1 inhibitors by cell biology experiments. The IC50 values of benbromarone, NP023335, TN1148, and TN1008 were 6.878, 18.46, 24.64, and 53.04 mu M, respectively. Molecular dynamics simulation was used to investigate the binding mechanism of URAT1 to NP023335, which forms stable contact with Ser35, Phe365, and Arg477. These interactions are essential for maintaining the biological activity of NP023335. The three compounds' pharmacokinetic characteristics were predicted, and NP023335's properties matched those of an empirical medication with the benefits of high solubility, low cardiotoxicity, good membrane permeability, and oral absorption. The natural product NP023335 will serve as a promising hit compound for facilitating the further design of novel URAT1 inhibitors.}, year = {2023}, eissn = {2046-2069}, pages = {3474-3486} } @article{MTMT:33822282, title = {AlphaFold2 and its applications in the fields of biology and medicine}, url = {https://m2.mtmt.hu/api/publication/33822282}, author = {Yang, Z. and Zeng, X. and Zhao, Y. and Chen, R.}, doi = {10.1038/s41392-023-01381-z}, journal-iso = {SIGNAL TRANSDUCT TAR}, journal = {SIGNAL TRANSDUCTION AND TARGETED THERAPY}, volume = {8}, unique-id = {33822282}, issn = {2095-9907}, year = {2023}, eissn = {2059-3635} } @article{MTMT:33076060, title = {TMbed: transmembrane proteins predicted through language model embeddings}, url = {https://m2.mtmt.hu/api/publication/33076060}, author = {Bernhofer, M. and Rost, B.}, doi = {10.1186/s12859-022-04873-x}, journal-iso = {BMC BIOINFORMATICS}, journal = {BMC BIOINFORMATICS}, volume = {23}, unique-id = {33076060}, issn = {1471-2105}, abstract = {Background: Despite the immense importance of transmembrane proteins (TMP) for molecular biology and medicine, experimental 3D structures for TMPs remain about 4–5 times underrepresented compared to non-TMPs. Today’s top methods such as AlphaFold2 accurately predict 3D structures for many TMPs, but annotating transmembrane regions remains a limiting step for proteome-wide predictions. Results: Here, we present TMbed, a novel method inputting embeddings from protein Language Models (pLMs, here ProtT5), to predict for each residue one of four classes: transmembrane helix (TMH), transmembrane strand (TMB), signal peptide, or other. TMbed completes predictions for entire proteomes within hours on a single consumer-grade desktop machine at performance levels similar or better than methods, which are using evolutionary information from multiple sequence alignments (MSAs) of protein families. On the per-protein level, TMbed correctly identified 94 ± 8% of the beta barrel TMPs (53 of 57) and 98 ± 1% of the alpha helical TMPs (557 of 571) in a non-redundant data set, at false positive rates well below 1% (erred on 30 of 5654 non-membrane proteins). On the per-segment level, TMbed correctly placed, on average, 9 of 10 transmembrane segments within five residues of the experimental observation. Our method can handle sequences of up to 4200 residues on standard graphics cards used in desktop PCs (e.g., NVIDIA GeForce RTX 3060). Conclusions: Based on embeddings from pLMs and two novel filters (Gaussian and Viterbi), TMbed predicts alpha helical and beta barrel TMPs at least as accurately as any other method but at lower false positive rates. Given the few false positives and its outstanding speed, TMbed might be ideal to sieve through millions of 3D structures soon to be predicted, e.g., by AlphaFold2. © 2022, The Author(s).}, keywords = {PROTEINS; Chemistry; Membrane Proteins; membrane protein; LANGUAGE; LANGUAGE; Forecasting; Molecular Biology; alpha helix; Computational linguistics; Databases, Protein; Embeddings; Embeddings; protein database; Protein structure prediction; Protein structure prediction; False positive rates; Language model; Transmembrane proteins; Protein prediction; transmembrane protein prediction; transmembrane protein prediction; 3D structure; Protein Conformation, alpha-Helical; Trans-membrane proteins; Protein language models; Protein language model}, year = {2022}, eissn = {1471-2105} } @article{MTMT:33427605, title = {Estimating conformational heterogeneity of tryptophan synthase with a template-based Alphafold2 approach}, url = {https://m2.mtmt.hu/api/publication/33427605}, author = {Casadevall, Guillem and Duran, Cristina and Estevez-Gay, Miquel and Osuna, Silvia}, doi = {10.1002/pro.4426}, journal-iso = {PROTEIN SCI}, journal = {PROTEIN SCIENCE}, volume = {31}, unique-id = {33427605}, issn = {0961-8368}, abstract = {The three-dimensional structure of the enzymes provides very relevant information on the arrangement of the catalytic machinery and structural elements gating the active site pocket. The recent success of the neural network Alphafold2 in predicting the folded structure of proteins from the primary sequence with high levels of accuracy has revolutionized the protein design field. However, the application of Alphafold2 for understanding and engineering function directly from the obtained single static picture is not straightforward. Indeed, understanding enzymatic function requires the exploration of the ensemble of thermally accessible conformations that enzymes adopt in solution. In the present study, we evaluate the potential of Alphafold2 in assessing the effect of the mutations on the conformational landscape of the beta subunit of tryptophan synthase (TrpB). Specifically, we develop a template-based Alphafold2 approach for estimating the conformational heterogeneity of several TrpB enzymes, which is needed for enhanced stand-alone activity. Our results show the potential of Alphafold2, especially if combined with molecular dynamics simulations, for elucidating the changes induced by mutation in the conformational landscapes at a rather reduced computational cost, thus revealing its plausible application in computational enzyme design.}, keywords = {tryptophan synthase; conformational heterogeneity; Computational enzyme design; AlphaFold2}, year = {2022}, eissn = {1469-896X}, orcid-numbers = {Casadevall, Guillem/0000-0003-4442-1600; Osuna, Silvia/0000-0003-3657-6469} } @article{MTMT:33427613, title = {Characterization of Three SEPALLATA-Like MADS-Box Genes Associated With Floral Development in Paphiopedilum henryanum (Orchidaceae)}, url = {https://m2.mtmt.hu/api/publication/33427613}, author = {Cheng, Hao and Xie, Xiulan and Ren, Maozhi and Yang, Shuhua and Zhao, Xin and Mahna, Nasser and Liu, Yi and Xu, Yufeng and Xiang, Yukai and Chai, Hua and Zheng, Liang and Ge, Hong and Jia, Ruidong}, doi = {10.3389/fpls.2022.916081}, journal-iso = {FRONT PLANT SCI}, journal = {FRONTIERS IN PLANT SCIENCE}, volume = {13}, unique-id = {33427613}, issn = {1664-462X}, abstract = {Paphiopedilum (Orchidaceae) is one of the world's most popular orchids that is found in tropical and subtropical forests and has an enormous ornamental value. SEPALLATA-like (SEP-like) MADS-box genes are responsible for floral organ specification. In this study, three SEP-like MADS-box genes, PhSEP1, PhSEP2, and PhSEP3, were identified in Paphiopedilum henryanum. These genes were 732-916 bp, with conserved SEPI and SEPII motifs. Phylogenetic analysis revealed that PhSEP genes were evolutionarily closer to the core eudicot SEP3 lineage, whereas none of them belonged to core eudicot SEP1/2/4 clades. PhSEP genes displayed non-ubiquitous expression, which was detectable across all floral organs at all developmental stages of the flower buds. Furthermore, subcellular localization experiments revealed the localization of PhSEP proteins in the nucleus. Yeast two-hybrid assays revealed no self-activation of PhSEPs. The protein-protein interactions revealed that PhSEPs possibly interact with B-class DEFICIENS-like and E-class MADS-box proteins. Our study suggests that the three SEP-like genes may play key roles in flower development in P. henryanum, which will improve our understanding of the roles of the SEP-like MADS-box gene family and provide crucial insights into the mechanisms underlying floral development in orchids.}, keywords = {expression analysis; flower development; gene cloning; Paphiopedilum; SEPALLATA-like MADS-box genes}, year = {2022}, eissn = {1664-462X} } @article{MTMT:33076030, title = {Structural mass spectrometry of membrane proteins}, url = {https://m2.mtmt.hu/api/publication/33076030}, author = {Dafun, A.S. and Marcoux, J.}, doi = {10.1016/j.bbapap.2022.140813}, journal-iso = {BBA-PROTEINS PROTEOM}, journal = {BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS}, volume = {1870}, unique-id = {33076030}, issn = {1570-9639}, abstract = {The analysis of proteins and protein complexes by mass spectrometry (MS) has come a long way since the invention of electrospray ionization (ESI) in the mid 80s. Originally used to characterize small soluble polypeptide chains, MS has progressively evolved over the past 3 decades towards the analysis of samples of ever increasing heterogeneity and complexity, while the instruments have become more and more sensitive and resolutive. The proofs of concepts and first examples of most structural MS methods appeared in the early 90s. However, their application to membrane proteins, key targets in the biopharma industry, is more recent. Nowadays, a wealth of information can be gathered from such MS-based methods, on all aspects of membrane protein structure: sequencing (and more precisely proteoform characterization), but also stoichiometry, non-covalent ligand binding (metals, drug, lipids, carbohydrates), conformations, dynamics and distance restraints for modelling. In this review, we present the concept and some historical and more recent applications on membrane proteins, for the major structural MS methods. © 2022 Elsevier B.V.}, keywords = {POLYPEPTIDE; ARTICLE; human; Chemistry; Membrane Proteins; Carbohydrate; membrane protein; membrane protein; METALS; METAL; Protein Conformation; Protein Stability; GLUTATHIONE TRANSFERASE; PROTEIN FUNCTION; unclassified drug; lipid; lipid bilayer; protein protein interaction; stoichiometry; proteomics; electric field; Spectrometry, Mass, Electrospray Ionization; electrospray mass spectrometry; ligand binding; protein structure; computer model; protein cross linking; covalent bond; protein quaternary structure; collisionally activated dissociation; protein assembly; Gel filtration; procedures; ion mobility spectrometry-mass spectrometry; native MS; hydrogen deuterium exchange-mass spectrometry; top-down MS; Covalent labelling MS; Cross-linking MS; Hydrogen-deuterium exchange MS; Ion-mobility MS; microsomal glutathione transferase 1}, year = {2022}, eissn = {1878-1454} } @article{MTMT:33822319, title = {Template-free prediction of a new monotopic membrane protein fold and assembly by AlphaFold2}, url = {https://m2.mtmt.hu/api/publication/33822319}, author = {Gulsevin, A. and Han, B. and Porta, J.C. and Mchaourab, H.S. and Meiler, J. and Kenworthy, A.K.}, doi = {10.1016/j.bpj.2022.11.011}, journal-iso = {BIOPHYS J}, journal = {BIOPHYSICAL JOURNAL}, unique-id = {33822319}, issn = {0006-3495}, year = {2022}, eissn = {1542-0086} } @article{MTMT:33596805, title = {Predicting the Assembly of the Transmembrane Domains of Viral Channel Forming Proteins and Peptide Drug Screening Using a Docking Approach}, url = {https://m2.mtmt.hu/api/publication/33596805}, author = {Huang, T.-C. and Fischer, W.B.}, doi = {10.3390/biom12121844}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {12}, unique-id = {33596805}, issn = {2218-273X}, year = {2022}, eissn = {2218-273X} } @article{MTMT:33427608, title = {An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms}, url = {https://m2.mtmt.hu/api/publication/33427608}, author = {Hunter, Gregory A. and Ferreira, Gloria C.}, doi = {10.3389/fmolb.2022.920668}, journal-iso = {FRONT MOL BIOSCI}, journal = {FRONTIERS IN MOLECULAR BIOSCIENCES}, volume = {9}, unique-id = {33427608}, abstract = {5-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5 & PRIME;-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in metazoa, fungi, and alpha-proteobacteria. ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled.}, keywords = {Regulation; porphyrin; Redox sensor; Allostery; 5-Aminolevulinate synthase; pyridoxal 5 '-phosphate; AlphaFold; heme regulatory motif}, year = {2022}, eissn = {2296-889X} } @article{MTMT:33427615, title = {Chemosynthetic ethanolamine plasmalogen stimulates gonadotropin secretion from bovine gonadotrophs by acting as a potential GPR61 agonist}, url = {https://m2.mtmt.hu/api/publication/33427615}, author = {Kadokawa, Hiroya and Yoshino, Ryunosuke and Saito, Risa and Hirokawa, Takatsugu}, doi = {10.1016/j.anireprosci.2022.106992}, journal-iso = {ANIM REPROD SCI}, journal = {ANIMAL REPRODUCTION SCIENCE}, volume = {241}, unique-id = {33427615}, issn = {0378-4320}, abstract = {Brain ethanolamine plasmalogens (EPls) are unique alkenylacyl-glycerophospholipids and the only recognized ligands of G-protein-coupled receptor 61 (GPR61), a newly identified receptor that colocalizes with GnRH receptors on gonadotrophs. As the chemical synthesis of EPl is challenging, only one chemosynthetic EPl, 1-(1Z-octadecenyl)- 2-oleoyl-sn-glycero-3-phosphoethanolamine (PLAPE; C18:0-C18:1), is commercially available. Therefore, we tested the hypothesis that PLAPE stimulates gonadotropin secretion from bovine gonadotrophs. We prepared anterior pituitary cells from healthy, post-pubertal heifers, cultured for 3.5 d, and then treated them with increasing concentrations (0, 0.5, 5, 50, or 500 pg/mL) of PLAPE for 5 mi, before either no treatment or GnRH stimulation. After 2 h, medium samples were harvested for FSH and LH assays. PLAPE (5-500 pg/mL) stimulated (P < 0.01) basal FSH and LH secretion, and such stimulation effects were inhibited by a SMAD pathway inhibitor. In the presence of GnRH, PLAPE at 0.5 and 5 pg/mL stimulated FSH and LH secretion (P < 0.01). However, a higher dose of PLAPE (500 pg/mL) suppressed GnRH-induced FSH and LH, and such suppressive effects were inhibited by an ERK pathway inhibitor. PLAPE stimulated gonadotropin secretion in the presence of EPls extracted from the brains of young heifers, but not old cows. Additionally, we performed in silico molecular-docking simulations using the deep-learning algorithm, AlphaFold2. The simulations revealed the presence of three binding sites for PLAPE in the three-dimensional structural model of GPR61. In conclusion, PLAPE stimulated gonadotropin secretion from bovine gonadotrophs and might act as a chemosynthetic agonist of GPR61.}, keywords = {luteinizing hormone; DRUG DISCOVERY; follicle-stimulating hormone; gonadotropin-releasing hormone receptor; Smad pathway; AlphaFold2}, year = {2022}, eissn = {1873-2232} } @article{MTMT:33427606, title = {Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb}, url = {https://m2.mtmt.hu/api/publication/33427606}, author = {Kwofie, Samuel K. and Hanson, George and Sasu, Henrietta and Enninful, Kweku S. and Mensah, Francis A. and Nortey, Richmond T. and Yeboah, Omane P. and Agoni, Clement and Wilson, Michael D.}, doi = {10.1002/cbdv.202200160}, journal-iso = {CHEM BIODIVERS}, journal = {CHEMISTRY & BIODIVERSITY}, volume = {19}, unique-id = {33427606}, issn = {1612-1872}, abstract = {Mycobacterial membrane proteins Large (MmpLs), which belong to the resistance, nodulation, and division (RND) protein superfamily, play critical roles in transporting polymers, lipids, and immunomodulators. MmpLs have become one of the important therapeutic drug targets to emerge in recent times. In this study, two homology modelling techniques, Modeller and SWISS-MODEL, were used in modelling the three-dimensional protein structure of the MmpL3 of Mycobacterium tuberculosis using that of M. smegmatis as template. MmpL3 inhibitors, namely BM212, NITD304, SPIRO, and NITD349, in addition to the co-crystalized ligands AU1235, ICA38, SQ109 and rimonabant, were screened against the modelled structure and the Mmpl3 of M. smegmatis using molecular docking techniques. Protein-ligand interactions were analysed using molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann surface area computations. Novel residues Gln32, Leu165, Ile414, and Phe35 were identified as critical for binding to M. tuberculosis MmpL3, and conformational dynamics upon inhibitor binding were discussed.}, keywords = {Mycobacterium tuberculosis; molecular dynamics simulations; Molecular docking; Mycobacterium smegmatis; mycobacterial membrane proteins large (MmpL3)}, year = {2022}, eissn = {1612-1880}, orcid-numbers = {Agoni, Clement/0000-0001-6130-8031} } @article{MTMT:33077594, title = {AlphaFold 2 and NMR Spectroscopy: Partners to Understand Protein Structure, Dynamics and Function}, url = {https://m2.mtmt.hu/api/publication/33077594}, author = {Laurents, D.V.}, doi = {10.3389/fmolb.2022.906437}, journal-iso = {FRONT MOL BIOSCI}, journal = {FRONTIERS IN MOLECULAR BIOSCIENCES}, volume = {9}, unique-id = {33077594}, abstract = {The artificial intelligence program AlphaFold 2 is revolutionizing the field of protein structure determination as it accurately predicts the 3D structure of two thirds of the human proteome. Its predictions can be used directly as structural models or indirectly as aids for experimental structure determination using X-ray crystallography, CryoEM or NMR spectroscopy. Nevertheless, AlphaFold 2 can neither afford insight into how proteins fold, nor can it determine protein stability or dynamics. Rare folds or minor alternative conformations are also not predicted by AlphaFold 2 and the program does not forecast the impact of post translational modifications, mutations or ligand binding. The remaining third of human proteome which is poorly predicted largely corresponds to intrinsically disordered regions of proteins. Key to regulation and signaling networks, these disordered regions often form biomolecular condensates or amyloids. Fortunately, the limitations of AlphaFold 2 are largely complemented by NMR spectroscopy. This experimental approach provides information on protein folding and dynamics as well as biomolecular condensates and amyloids and their modulation by experimental conditions, small molecules, post translational modifications, mutations, flanking sequence, interactions with other proteins, RNA and virus. Together, NMR spectroscopy and AlphaFold 2 can collaborate to advance our comprehension of proteins. Copyright © 2022 Laurents.}, keywords = {NMR spectroscopy; POSTTRANSLATIONAL MODIFICATIONS; AlphaFold; Intrisically disordered proteins; Rare conformations}, year = {2022}, eissn = {2296-889X} } @article{MTMT:33076346, title = {The pH sensor and ion binding of NhaD Na+/H+ antiporter from IT superfamily}, url = {https://m2.mtmt.hu/api/publication/33076346}, author = {Lv, P. and Li, Y. and Wang, R. and Zhang, Y. and Wang, W. and Liu, Y. and Shang, Y. and Su, D. and Wang, W. and Yang, C.}, doi = {10.1111/mmi.14965}, journal-iso = {MOL MICROBIOL}, journal = {MOLECULAR MICROBIOLOGY}, unique-id = {33076346}, issn = {0950-382X}, abstract = {Sodium-proton (Na+/H+) antiporters from the ion transporter (IT) superfamily play a vital role in controlling the pH and electrolyte homeostasis. However, very limited information regarding their structural functions is available to date. In this study, the structural model of the NhaD antiporter was proposed as a typical hairpin structure of IT proteins, with two symmetrically conserved scaffold domains that frame the core substrate-binding sites, and four motifs were identified. Furthermore, 25 conserved sites involving these domains were subjected to site-directed mutagenesis, and all mutations resulted in an impact on transport abilities. In particular, as candidates for Na+-binding sites, D166 and D405 mutations at hairpin discontinuities were detrimental to transport activities and were found to induce pronounced conformational changes using fluorescence resonance energy transfer (FRET) assays. In addition, as observed in the NhaA structure, some charged residues, for example, E64, E65, R454, and R464, are predicted to be involved in the net charge switch of NhaD activation, by collectively form a “pH sensor” at the entrance of the cytoplasmic funnel. Mutations encompassing these residues were detrimental to the transport activity of NhaD or lost the capacity to respond to pH signals and trigger conformational changes for Na+ translocation. © 2022 John Wiley & Sons Ltd.}, keywords = {NhaD antiporter; pH sensor; helical hairpins; IT superfamily; substrate binding scaffold}, year = {2022}, eissn = {1365-2958} } @article{MTMT:33427604, title = {Structural basis for the arsenite binding and translocation of Acr3 antiporter with NhaA folding pattern}, url = {https://m2.mtmt.hu/api/publication/33427604}, author = {Lv, Peiwen and Shang, Yan and Zhang, Ye and Wang, Wenkai and Liu, Yuanxiang and Su, Dandan and Wang, Wei and Li, Chunfang and Ma, Cuiqing and Yang, Chunyu}, doi = {10.1096/fj.202201280R}, journal-iso = {FASEB J}, journal = {FASEB JOURNAL}, volume = {36}, unique-id = {33427604}, issn = {0892-6638}, abstract = {The arsenical resistance-3 (ACR3) family constitutes the most common pathway that confers high-level resistance to toxic metalloids in various microorganisms and lower plants. Based on the structural model constructed by AlphaFold2, the Acr3 antiporter from Bacillus subtilis (Acr3(Bs)) exhibits a typical NhaA structure fold, with two discontinuous helices of transmembrane (TM) segments, TM4 and TM9, interacting with each other and forming an X-shaped structure. As the structural information available for these important arsenite-efflux pumps is limited, we investigated the evolutionary conservation among 300 homolog sequences and identified three conserved motifs in both the discontinuous helices and TM5. Through site-directed mutagenesis, microscale thermophoresis (MST), and fluorescence resonance energy transfer (FRET) analyses, the identified Motif C in TM9 was found to be a critical element for substrate binding, in which N292 and E295 are involved in substrate coordination, while R118 in TM4 and E322 in TM10 is responsible for structural stabilization. In addition, the highly conserved residues on Motif B of TM5 are potentially key factors in the protonation/deprotonation process. These consensus motifs and residues are essential for metalloid compound translocation of Acr3 antiporters, by framing the core domain and the typical X-shaped of NhaA fold.}, keywords = {FRET; SITE-DIRECTED MUTAGENESIS; Bacillus subtilis; antiporter; structural model; Arsenite}, year = {2022}, eissn = {1530-6860} } @inproceedings{MTMT:33822317, title = {A Bioinformatics Pipeline for the identification of disease-causing variants in humans that can change protein structure}, url = {https://m2.mtmt.hu/api/publication/33822317}, author = {Ma, M. and Hou, I. and Gao, J. and Li, C. and Bai, Y. and Liu, X.}, booktitle = {2022 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)}, doi = {10.1109/BIBM55620.2022.9995589}, unique-id = {33822317}, year = {2022}, pages = {3849-3851} } @article{MTMT:33427616, title = {Computational Saturation Mutagenesis to Investigate the Effects of Neurexin-1 Mutations on AlphaFold Structure}, url = {https://m2.mtmt.hu/api/publication/33427616}, author = {Rhoades, Raina and Henry, Brianna and Prichett, Dominique and Fang, Yayin and Teng, Shaolei}, doi = {10.3390/genes13050789}, journal-iso = {GENES-BASEL}, journal = {GENES}, volume = {13}, unique-id = {33427616}, issn = {2073-4425}, abstract = {Neurexin-1 (NRXN1) is a membrane protein essential in synapse formation and cell signaling as a cell-adhesion molecule and cell-surface receptor. NRXN1 and its binding partner neuroligin have been associated with deficits in cognition. Recent genetics research has linked NRXN1 missense mutations to increased risk for brain disorders, including schizophrenia (SCZ) and autism spectrum disorder (ASD). Investigation of the structure-function relationship in NRXN1 has proven difficult due to a lack of the experimental full-length membrane protein structure. AlphaFold, a deep learning-based predictor, succeeds in high-quality protein structure prediction and offers a solution for membrane protein model construction. In the study, we applied a computational saturation mutagenesis method to analyze the systemic effects of missense mutations on protein functions in a human NRXN1 structure predicted from AlphaFold and an experimental Bos taurus structure. The folding energy changes were calculated to estimate the effects of the 29,540 mutations of AlphaFold model on protein stability. The comparative study on the experimental and computationally predicted structures shows that these energy changes are highly correlated, demonstrating the reliability of the AlphaFold structure for the downstream bioinformatics analysis. The energy calculation revealed that some target mutations associated with SCZ and ASD could make the protein unstable. The study can provide helpful information for characterizing the disease-causing mutations and elucidating the molecular mechanisms by which the variations cause SCZ and ASD. This methodology could provide the bioinformatics protocol to investigate the effects of target mutations on multiple AlphaFold structures.}, keywords = {Protein Stability; missense mutation; AlphaFold; computational saturation mutagenesis; Neurexin-1}, year = {2022}, eissn = {2073-4425}, orcid-numbers = {Rhoades, Raina/0000-0001-6241-0513} } @article{MTMT:33427618, title = {Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation}, url = {https://m2.mtmt.hu/api/publication/33427618}, author = {Sekar, Giridhar and Ojoawo, Adedolapo and Moldoveanu, Tudor}, doi = {10.1042/BST20220323}, journal-iso = {BIOCHEM SOC T}, journal = {BIOCHEMICAL SOCIETY TRANSACTIONS}, volume = {50}, unique-id = {33427618}, issn = {0300-5127}, abstract = {Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions. The BCL-2 family proteins function in protein-protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein-protein and protein-lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular alpha-helical proteins that participate in protein-protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein-protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein-protein interaction complexes of BCL-2 family proteins.}, year = {2022}, eissn = {1470-8752}, pages = {1091-1103}, orcid-numbers = {Ojoawo, Adedolapo/0000-0003-3961-8935} } @article{MTMT:33822304, title = {Characteristics of the GlnH and GlnX Signal Transduction Proteins Controlling PknG-Mediated Phosphorylation of OdhI and 2-Oxoglutarate Dehydrogenase Activity in Corynebacterium glutamicum}, url = {https://m2.mtmt.hu/api/publication/33822304}, author = {Sundermeyer, L. and Bosco, G. and Gujar, S. and Brocker, M. and Baumgart, M. and Willbold, D. and Weiergräber, O.H. and Bellinzoni, M. and Bott, M.}, doi = {10.1128/spectrum.02677-22}, journal-iso = {MICROBIOL SPEC}, journal = {MICROBIOLOGY SPECTRUM}, volume = {10}, unique-id = {33822304}, issn = {2165-0497}, year = {2022}, eissn = {2165-0497} } @article{MTMT:33084278, title = {Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology}, url = {https://m2.mtmt.hu/api/publication/33084278}, author = {Tordai, Hedvig and Suhajda, Erzébet and Sillitoe, Ian and Nair, Sreenath and Varadi, Mihaly and Hegedűs, Tamás}, doi = {10.3390/ijms23168877}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33084278}, issn = {1661-6596}, abstract = {The number of unique transmembrane (TM) protein structures doubled in the last four years, which can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using the PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.}, keywords = {MECHANISM; CLASSIFICATION; MUTATIONS; CHANNEL; P-GLYCOPROTEIN; TRANSPORTERS; protein structure; inventory; ABC TRANSPORTERS; PROTEIN COMPLEX; Biochemistry & Molecular Biology; Structure database; AlphaFold2; AF-multimer}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Tordai, Hedvig/0000-0002-0875-5569; Varadi, Mihaly/0000-0002-3687-0839; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:33618143, title = {Functionally annotating cysteine disulfides and metal binding sites in the plant kingdom using AlphaFold2 predicted structures}, url = {https://m2.mtmt.hu/api/publication/33618143}, author = {Willems, Patrick and Huang, Jingjing and Messens, Joris and Van, Breusegem Frank}, doi = {10.1016/j.freeradbiomed.2022.12.001}, journal-iso = {FREE RADICAL BIO MED}, journal = {FREE RADICAL BIOLOGY AND MEDICINE}, volume = {194}, unique-id = {33618143}, issn = {0891-5849}, abstract = {Deep learning algorithms such as AlphaFold2 predict three-dimensional protein structure with high confidence. The recent release of more than 200 million structural models provides an unprecedented resource for functional protein annotation. Here, we used AlphaFold2 predicted structures of fifteen plant proteomes to functionally and evolutionary analyze cysteine residues in the plant kingdom. In addition to identification of metal ligands co-ordinated by cysteine residues, we systematically analyzed cysteine disulfides present in these structural pre-dictions. Our analysis demonstrates most of these predicted disulfides are trustworthy due their high agreement (-96%) with those present in X-ray and NMR protein structures, their characteristic disulfide stereochemistry, the biased subcellular distribution of their proteins and a higher degree of oxidation of their respective cysteines as measured by proteomics. Adopting an evolutionary perspective, zinc binding sites are increasingly present at the expense of iron-sulfur clusters in plants. Interestingly, disulfide formation is increased in secreted proteins of land plants, likely promoting sequence evolution to adapt to changing environments encountered by plants. In summary, Alphafold2 predicted structural models are a rich source of information for studying the role of cys-teines residues in proteins of interest and for protein redox biology in general.}, keywords = {PROTEINS; DOMAINS; PLANTS; EFFICIENT; CYSTEINE; RESOURCE; BONDS; Disulfides; Biochemistry & Molecular Biology; Redox regulation; END RULE PATHWAY; complexity; streptophyte algae; AlphaFold2; metal ligand}, year = {2022}, eissn = {1873-4596}, pages = {220-229}, orcid-numbers = {Willems, Patrick/0000-0003-4667-2294; Huang, Jingjing/0000-0002-4963-3162} } @article{MTMT:33427610, title = {Renewable nitrogen-containing products by Maillard reaction of sewage sludge and glucose. Part I. Analysis of nitrogen composition and protein model based on AlphaFold2}, url = {https://m2.mtmt.hu/api/publication/33427610}, author = {Zhai, Jinpeng and Han, Xiangxin and Zhai, Guohao and Jiang, Xiumin}, doi = {10.1016/j.fuel.2022.124968}, journal-iso = {FUEL}, journal = {FUEL}, volume = {325}, unique-id = {33427610}, issn = {0016-2361}, abstract = {In order to better understand the nitrogen transformation in Maillard reaction during the co-pyrolysis of sewage sludge (SS) and glucose, analysis of Maillard reaction-related nitrogen-containing compounds (NCCs) and the protein model of SS is proposed. The composition, content, and structure of NCCs, especially protein in SS, are critical for the investigation of nitrogen transformation in Maillard reaction. The distribution and relative content of Maillard reaction-related functional groups, NCCs, and amino acids in SS were studied. Genomes by DNA sequencing are further applied in building a database search for metaproteomic studies, which provide valuable information and insight into the origin of SS protein, such as the taxonomic composition of the underlying microbial community, inferred protein functions, and their relationship with the transformation of NCCs. SS protein model was constructed by Alphafold2, and key factors determining the selection of SS protein model were revealed.}, keywords = {Sewage sludge; Protein identification; protein model; nitrogen-containing compounds; AlphaFold2}, year = {2022}, eissn = {1873-7153} }