@article{MTMT:31953886,
	title = {The incredible diversity of structures and functions of ABC transporters},
	url = {https://m2.mtmt.hu/api/publication/31953886},
	author = {Hamdoun, A. and Hellmich, U.A. and Szakács, Gergely and Kuchler, K.},
	doi = {10.1002/1873-3468.14061},
	journal-iso = {FEBS LETT},
	journal = {FEBS LETTERS},
	volume = {595},
	unique-id = {31953886},
	issn = {0014-5793},
	keywords = {CLASSIFICATION; human; editorial; priority journal; nonhuman; Cryoelectron Microscopy; Homeostasis; PROTEIN FUNCTION; Environment; protein structure; ABC transporter},
	year = {2021},
	eissn = {1873-3468},
	pages = {671-674}
}

@article{MTMT:31623716,
	title = {The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations},
	url = {https://m2.mtmt.hu/api/publication/31623716},
	author = {Nagy, Tamás and Tóth, Ágota and Telbisz, Ágnes Mária and Sarkadi, Balázs and Tordai, Hedvig and Tordai, Attila and Hegedűs, Tamás},
	doi = {10.1007/s00018-020-03651-3},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {78},
	unique-id = {31623716},
	issn = {1420-682X},
	abstract = {Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions. © 2020, The Author(s).},
	keywords = {ABCG2; molecular dynamics; cholesterol regulation; Multidrug transport},
	year = {2021},
	eissn = {1420-9071},
	pages = {2329-2339},
	orcid-numbers = {Nagy, Tamás/0000-0002-0137-4341; Tóth, Ágota/0000-0003-1376-5291; Telbisz, Ágnes Mária/0000-0003-0972-4606; Sarkadi, Balázs/0000-0003-0592-4539; Tordai, Hedvig/0000-0002-0875-5569; Tordai, Attila/0000-0001-6966-1622; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:30745347,
	title = {Discovering the chloride pathway in the CFTR channel},
	url = {https://m2.mtmt.hu/api/publication/30745347},
	author = {Farkas, Bianka Vivien and Tordai, Hedvig and Padányi, Rita and Tordai, Attila and Gera, János and Paragi, Gábor and Hegedűs, Tamás},
	doi = {10.1007/s00018-019-03211-4},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {77},
	unique-id = {30745347},
	issn = {1420-682X},
	year = {2020},
	eissn = {1420-9071},
	pages = {765-778},
	orcid-numbers = {Farkas, Bianka Vivien/0000-0002-0258-6864; Tordai, Hedvig/0000-0002-0875-5569; Padányi, Rita/0000-0001-7798-0463; Tordai, Attila/0000-0001-6966-1622; Paragi, Gábor/0000-0001-5408-1748; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:31634543,
	title = {The ABCG2/BCRP transporter and its variants - from structure to pathology},
	url = {https://m2.mtmt.hu/api/publication/31634543},
	author = {Sarkadi, Balázs and Homolya, László and Hegedűs, Tamás},
	doi = {10.1002/1873-3468.13947},
	journal-iso = {FEBS LETT},
	journal = {FEBS LETTERS},
	volume = {594},
	unique-id = {31634543},
	issn = {0014-5793},
	abstract = {The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.},
	keywords = {VARIANTS; ABCG2; TRAFFICKING; Drug Resistance; drug metabolism; gout; molecular dynamics},
	year = {2020},
	eissn = {1873-3468},
	pages = {4012-4034},
	orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539; Homolya, László/0000-0003-1639-8140; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:31664473,
	title = {Structural and functional diversity calls for a new classification of ABC transporters},
	url = {https://m2.mtmt.hu/api/publication/31664473},
	author = {Thomas, C. and Aller, S.G. and Beis, K. and Carpenter, E.P. and Chang, G. and Chen, L. and Dassa, E. and Dean, M. and Duong, Van Hoa F. and Ekiert, D. and Ford, R. and Gaudet, R. and Gong, X. and Holland, I.B. and Huang, Y. and Kahne, D.K. and Kato, H. and Koronakis, V. and Koth, C.M. and Lee, Y. and Lewinson, O. and Lill, R. and Martinoia, E. and Murakami, S. and Pinkett, H.W. and Poolman, B. and Rosenbaum, D. and Sarkadi, Balázs and Schmitt, L. and Schneider, E. and Shi, Y. and Shyng, S.-L. and Slotboom, D.J. and Tajkhorshid, E. and Tieleman, D.P. and Ueda, K. and Váradi, András and Wen, P.-C. and Yan, N. and Zhang, P. and Zheng, H. and Zimmer, J. and Tampé, R.},
	doi = {10.1002/1873-3468.13935},
	journal-iso = {FEBS LETT},
	journal = {FEBS LETTERS},
	volume = {594},
	unique-id = {31664473},
	issn = {0014-5793},
	abstract = {Members of the ATP-binding cassette (ABC) transporter superfamily translocate a broad spectrum of chemically diverse substrates. While their eponymous ATP-binding cassette in the nucleotide-binding domains (NBDs) is highly conserved, their transmembrane domains (TMDs) forming the translocation pathway exhibit distinct folds and topologies, suggesting that during evolution the ancient motor domains were combined with different transmembrane mechanical systems to orchestrate a variety of cellular processes. In recent years, it has become increasingly evident that the distinct TMD folds are best suited to categorize the multitude of ABC transporters. We therefore propose a new ABC transporter classification that is based on structural homology in the TMDs. © 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies},
	keywords = {PHYLOGENY; Membrane Proteins; Sequence Alignment; X-RAY CRYSTALLOGRAPHY; ABC TRANSPORTERS; Structural biology; cryo-EM; ATPASES; molecular machines; primary active transporters},
	year = {2020},
	eissn = {1873-3468},
	pages = {3767-3775},
	orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539}
}

@article{MTMT:30387986,
	title = {STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL.},
	url = {https://m2.mtmt.hu/api/publication/30387986},
	author = {Csanády, László and Vergani, Paola and Gadsby, David C},
	doi = {10.1152/physrev.00007.2018},
	journal-iso = {PHYSIOL REV},
	journal = {PHYSIOLOGICAL REVIEWS},
	volume = {99},
	unique-id = {30387986},
	issn = {0031-9333},
	abstract = {The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP-dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo-electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed.},
	year = {2019},
	eissn = {1522-1210},
	pages = {707-738},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:3210856,
	title = {Molecular Structure of the Human CFTR Ion Channel},
	url = {https://m2.mtmt.hu/api/publication/3210856},
	author = {Liu, F and Zhang, Z and Csanády, László and Gadsby, DC and Chen, J},
	doi = {10.1016/j.cell.2017.02.024},
	journal-iso = {CELL},
	journal = {CELL},
	volume = {169},
	unique-id = {3210856},
	issn = {0092-8674},
	abstract = {The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding cassette (ABC) transporter that uniquely functions as an ion channel. Here, we present a 3.9 Å structure of dephosphorylated human CFTR without nucleotides, determined by electron cryomicroscopy (cryo-EM). Close resemblance of this human CFTR structure to zebrafish CFTR under identical conditions reinforces its relevance for understanding CFTR function. The human CFTR structure reveals a previously unresolved helix belonging to the R domain docked inside the intracellular vestibule, precluding channel opening. By analyzing the sigmoid time course of CFTR current activation, we propose that PKA phosphorylation of the R domain is enabled by its infrequent spontaneous disengagement, which also explains residual ATPase and gating activity of dephosphorylated CFTR. From comparison with MRP1, a feature distinguishing CFTR from all other ABC transporters is the helix-loop transition in transmembrane helix 8, which likely forms the structural basis for CFTR's channel function. © 2017 Elsevier Inc.},
	keywords = {ABC transporter; anion channel; human CFTR; cryo-EM},
	year = {2017},
	eissn = {1097-4172},
	pages = {85-95.e8},
	orcid-numbers = {Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:3135666,
	title = {Jump into a new fold-A homology based model for the ABCG2/BCRP multidrug transporter},
	url = {https://m2.mtmt.hu/api/publication/3135666},
	author = {László, L and Sarkadi, Balázs and Hegedűs, Tamás},
	doi = {10.1371/journal.pone.0164426},
	journal-iso = {PLOS ONE},
	journal = {PLOS ONE},
	volume = {11},
	unique-id = {3135666},
	issn = {1932-6203},
	abstract = {ABCG2/BCRP is a membrane protein, involved in xenobiotic and endobiotic transport in key pharmacological barriers and drug metabolizing organs, in the protection of stem cells, and in multidrug resistance of cancer. Pharmacogenetic studies implicated the role of ABCG2 in response to widely used medicines and anticancer agents, as well as in gout. Its Q141K variant exhibits decreased functional expression thus increased drug accumulation and decreased urate secretion. Still, there has been no reliable molecular model available for this protein, as the published structures of other ABC transporters could not be properly fitted to the ABCG2 topology and experimental data. The recently published high resolution structure of a close homologue, the ABCG5-ABCG8 heterodimer, revealed a new ABC transporter fold, unique for ABCG proteins. Here we present a structural model of the ABCG2 homodimer based on this fold and detail the experimental results supporting this model. In order to describe the effect of mutations on structure and dynamics, and characterize substrate recognition and cholesterol regulation we performed molecular dynamics simulations using full length ABCG2 protein embedded in a membrane bilayer and in silico docking simulations. Our results show that in the Q141K variant the introduced positive charge diminishes the interaction between the nucleotide binding and transmembrane domains and the R482G variation alters the orientation of transmembrane helices. Moreover, the R482 position, which plays a role the substrate specificity of the transporter, is located in one of the substrate binding pockets identified by the in silico docking calculations. In summary, the ABCG2 model and in silico simulations presented here may have significant impact on understanding drug distribution and toxicity, as well as drug development against cancer chemotherapy resistance or gout. © 2016 László et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.},
	year = {2016},
	eissn = {1932-6203},
	orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:25803207,
	title = {From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations},
	url = {https://m2.mtmt.hu/api/publication/25803207},
	author = {Veit, Gudio and Avramescu, Radu G and Chiang, Annette N and Houck, Scott A and Cai, Zhiwei and Peters, Kathryn W and Hong, Jeong S and Pollard, Harvey B and Guggino, William B and Balch, William E and Skach, William R and Cutting, Garry R and Frizzell, Raymond A and Sheppard, David N and Cyr, Douglas M and Sorscher, Eric J and Brodsky, Jeffrey L and Lukács, Gergely},
	doi = {10.1091/mbc.E14-04-0935},
	journal-iso = {MOL BIOL CELL},
	journal = {MOLECULAR BIOLOGY OF THE CELL},
	volume = {27},
	unique-id = {25803207},
	issn = {1059-1524},
	year = {2016},
	eissn = {1939-4586},
	pages = {424-433}
}

@article{MTMT:2918485,
	title = {CCTOP: a Consensus Constrained TOPology prediction web server.},
	url = {https://m2.mtmt.hu/api/publication/2918485},
	author = {Dobson, László and Reményi, István and Tusnády, Gábor},
	doi = {10.1093/nar/gkv451},
	journal-iso = {NUCLEIC ACIDS RES},
	journal = {NUCLEIC ACIDS RESEARCH},
	volume = {43},
	unique-id = {2918485},
	issn = {0305-1048},
	year = {2015},
	eissn = {1362-4962},
	pages = {W408-W412},
	orcid-numbers = {Reményi, István/0000-0003-4670-2406}
}

@article{MTMT:2905250,
	title = {The human transmembrane proteome},
	url = {https://m2.mtmt.hu/api/publication/2905250},
	author = {Dobson, László and Reményi, István and Tusnády, Gábor},
	doi = {10.1186/s13062-015-0061-x},
	journal-iso = {BIOL DIRECT},
	journal = {BIOLOGY DIRECT},
	volume = {10},
	unique-id = {2905250},
	issn = {1745-6150},
	abstract = {Background: Transmembrane proteins have important roles in cells, as they are involved in energy production, signal transduction, cell-cell interaction, cell-cell communication and more. In human cells, they are frequently targets for pharmaceuticals; therefore, knowledge about their properties and structure is crucial. Topology of transmembrane proteins provide a low resolution structural information, which can be a starting point for either laboratory experiments or modelling their 3D structures. Results: Here, we present a database of the human α-helical transmembrane proteome, including the predicted and/or experimentally established topology of each transmembrane protein, together with the reliability of the prediction. In order to distinguish transmembrane proteins in the proteome as well as for topology prediction, we used a newly developed consensus method (CCTOP) that incorporates recent state of the art methods, with tested accuracies on a novel human benchmark protein set. CCTOP utilizes all available structure and topology data as well as bioinformatical evidences for topology prediction in a probabilistic framework provided by the hidden Markov model. This method shows the highest accuracy (98.5 % for discrinimating between transmembrane and non-transmembrane proteins and 84 % for per protein topology prediction) among the dozen tested topology prediction methods. Analysis of the human proteome with the CCTOP indicates that it contains 4998 (26 %) transmembrane proteins. Besides predicting topology, reliability of the predictions is estimated as well, and it is demonstrated that the per protein prediction accuracies of more than 60 % of the predictions are over 98 % on the benchmark sets and most probably on the predicted human transmembrane proteome too. Conclusions: Here, we present the most accurate prediction of the human transmembrane proteome together with the experimental topology data. These data, as well as various statistics about the human transmembrane proteins and their topologies can be downloaded from and can be visualized at the website of the human transmembrane proteome (http://htp.enzim.hu). Reviewers: This article was reviewed by Dr. Sandor Pongor, Dr. Michael Galperin and Dr. Pascale Gaudet (nominated by Dr Michael Galperin). © 2015 Dobson et al.; licensee BioMed Central.},
	keywords = {Hidden Markov model; TOPOLOGY PREDICTION; transmembrane protein; Constrained prediction},
	year = {2015},
	eissn = {1745-6150},
	orcid-numbers = {Reményi, István/0000-0003-4670-2406}
}

@article{MTMT:2149788,
	title = {PDBTM: Protein Data Bank of transmembrane proteins after 8 years},
	url = {https://m2.mtmt.hu/api/publication/2149788},
	author = {Kozma, Dániel and Simon, István and Tusnády, Gábor},
	doi = {10.1093/nar/gks1169},
	journal-iso = {NUCLEIC ACIDS RES},
	journal = {NUCLEIC ACIDS RESEARCH},
	volume = {41},
	unique-id = {2149788},
	issn = {0305-1048},
	year = {2013},
	eissn = {1362-4962},
	pages = {D524-D529}
}

@article{MTMT:1506345,
	title = {Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding.},
	url = {https://m2.mtmt.hu/api/publication/1506345},
	author = {Serohijos, AW and Hegedűs, Tamás and Riordan, JR and Dokholyan, NV},
	doi = {10.1371/journal.pcbi.1000008},
	journal-iso = {PLOS COMPUT BIOL},
	journal = {PLOS COMPUTATIONAL BIOLOGY},
	volume = {4},
	unique-id = {1506345},
	issn = {1553-734X},
	abstract = {The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of NBD1-DeltaF508 are essential information in correcting this pathogenic mutant.},
	keywords = {MUTATION; computer simulation; amino acid substitution; *Models, Molecular; Protein Folding; structure-activity relationship; Protein Conformation; Protein Denaturation; *Models, Chemical; Molecular Chaperones/*chemistry/*ultrastructure; Regulator/*chemistry/genetics/*ultrastructure; Cystic Fibrosis Transmembrane Conductance},
	year = {2008},
	eissn = {1553-7358},
	pages = {e1000008},
	orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:151391,
	title = {Characterization of the amino-terminal regions in the human multidrug resistance protein (MRP1)},
	url = {https://m2.mtmt.hu/api/publication/151391},
	author = {Bakos, Éva and Evers, R and Calenda, G and Tusnády, Gábor and Szakács, Gergely and Váradi, András and Sarkadi, Balázs},
	journal-iso = {J CELL SCI},
	journal = {JOURNAL OF CELL SCIENCE},
	volume = {113},
	unique-id = {151391},
	issn = {0021-9533},
	abstract = {The human multidrug resistance protein (MRP1) contributes to drug resistance in cancer cells. In addition to an MDR1-like core, MRP1 contains an N-terminal membrane-bound (TMD0) region and a cytoplasmic linker (L0), both characteristic of several members of the MRP family. In order to study the role of the TMD0 and L0 regions, we constructed various truncated and mutated MRP1, and chimeric MRP1-MDR1 molecules, which were expressed in insect (Sf9) and polarized mammalian (MDCKII) cells. The function of the various proteins was examined in isolated membrane vesicles by measuring the transport of leukotriene C4 and other glutathione conjugates, and by vanadate-dependent nucleotide occlusion. Cellular localization, and glutathione-conjugate and drug transport, were also studied in MDCKII cells. We found that chimeric proteins consisting of N-terminal fragments of MRP1 fused to the N terminus of MDR1 preserved the transport, nucleotide occlusion and apical membrane routing of wild-type MDR1. As shown before, MRP1 without TMD0L0 (ΔMRP1), was non-functional and localized intracellularly, so we investigated the coexpression of ΔMRP1 with the isolated L0 region. Coexpression yielded a functional MRP1 molecule in Sf9 cells and routing to the lateral membrane in MDCKII cells. Interestingly, the L0 peptide was found to be associated with membranes in Sf9 cells and could only be solubilized by urea or detergent. A 10-amino-acid deletion in a predicted amphipathic region of L0 abolished its attachment to the membrane and eliminated MRP1 transport function, but did not affect membrane routing. Taken together, these experiments suggest that the L0 region forms a distinct domain within MRP1, which interacts with hydrophobic membrane regions and with the core region of MRP1.},
	year = {2000},
	eissn = {1477-9137},
	pages = {4451-4461},
	orcid-numbers = {Sarkadi, Balázs/0000-0003-0592-4539}
}