TY - JOUR AU - Hegedűs, Tamás AU - Geisler, Markus AU - Lukács, Gergely László AU - Farkas, Bianka Vivien TI - Ins and outs of AlphaFold2 transmembrane protein structure predictions JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 79 PY - 2022 IS - 1 PG - 12 SN - 1420-682X DO - 10.1007/s00018-021-04112-1 UR - https://m2.mtmt.hu/api/publication/32612583 ID - 32612583 LA - English DB - MTMT ER - TY - JOUR AU - Hegyi, Zoltán AU - Hegedűs, Tamás AU - Homolya, László TI - The Reentry Helix Is Potentially Involved in Cholesterol Sensing of the ABCG1 Transporter Protein JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 22 PG - 16 SN - 1661-6596 DO - 10.3390/ijms232213744 UR - https://m2.mtmt.hu/api/publication/33293571 ID - 33293571 LA - English DB - MTMT ER - TY - JOUR AU - Padányi, Rita AU - Farkas, Bianka Vivien AU - Tordai, Hedvig AU - Kiss, Bálint AU - Grubmüller, Helmut AU - Soya, Naoto AU - Lukács, Gergely L. AU - Kellermayer, Miklós AU - Hegedűs, Tamás TI - Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1 JF - COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL J2 - CSBJ VL - 20 PY - 2022 SP - 2587 EP - 2599 PG - 13 SN - 2001-0370 DO - 10.1016/j.csbj.2022.05.036 UR - https://m2.mtmt.hu/api/publication/32853643 ID - 32853643 LA - English DB - MTMT ER - TY - JOUR AU - Tordai, Hedvig AU - Suhajda, Erzébet AU - Sillitoe, Ian AU - Nair, Sreenath AU - Varadi, Mihaly AU - Hegedűs, Tamás TI - Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 16 PG - 16 SN - 1661-6596 DO - 10.3390/ijms23168877 UR - https://m2.mtmt.hu/api/publication/33084278 ID - 33084278 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Varadi, M. AU - Nair, S. AU - Sillitoe, I. AU - Tauriello, G. AU - Anyango, S. AU - Bienert, S. AU - Borges, C. AU - Deshpande, M. AU - Green, T. AU - Hassabis, D. AU - Hatos, András AU - Hegedűs, Tamás AU - Hekkelman, M.L. AU - Joosten, R. AU - Jumper, J. AU - Laydon, A. AU - Molodenskiy, D. AU - Piovesan, D. AU - Salladini, E. AU - Salzberg, S.L. AU - Sommer, M.J. AU - Steinegger, M. AU - Suhajda, E. AU - Svergun, D. AU - Tenorio-Ku, L. AU - Tosatto, S. AU - Tunyasuvunakool, K. AU - Waterhouse, A.M. AU - Žídek, A. AU - Schwede, T. AU - Orengo, C. AU - Velankar, S. TI - 3D-Beacons: decreasing the gap between protein sequences and structures through a federated network of protein structure data resources JF - GIGASCIENCE J2 - GIGASCIENCE VL - 11 PY - 2022 IS - 1 PG - 8 SN - 2047-217X DO - 10.1093/gigascience/giac118 UR - https://m2.mtmt.hu/api/publication/33315002 ID - 33315002 LA - English DB - MTMT ER - TY - JOUR AU - Földi, Mátyás Csaba AU - Pesti, Krisztina AU - Zboray, Katalin AU - Tóth, Ádám Viktor AU - Hegedűs, Tamás AU - Málnási Csizmadia, András AU - Lukács, Péter AU - Mike, Árpád TI - The mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling JF - BRITISH JOURNAL OF PHARMACOLOGY J2 - BR J PHARMACOL VL - 178 PY - 2021 IS - 5 SP - 1200 EP - 1217 PG - 18 SN - 0007-1188 DO - 10.1111/bph.15365 UR - https://m2.mtmt.hu/api/publication/31821613 ID - 31821613 N1 - MTA-ELTE NAP B Opto-Neuropharmacology Group, Budapest, Hungary Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary School of PhD Studies, Semmelweis University, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Motor Pharmacology Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary Export Date: 20 March 2021 CODEN: BJPCB Correspondence Address: Mike, A.; MTA-ELTE NAP B Opto-Neuropharmacology GroupHungary; email: arpadmike1@gmail.com Correspondence Address: Mike, A.; Plant Protection Institute, Hungary; email: arpadmike1@gmail.com Correspondence Address: Mike, A.; Department of Biochemistry, Hungary; email: arpadmike1@gmail.com Funding details: KTIA‐NAP‐13‐2‐2014‐002 Funding details: GINOP‐2.3.2‐15‐2016‐00051 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, K127961 Funding text 1: This work was supported by the Hungarian Brain Research Program (KTIA‐NAP‐13‐2‐2014‐002), Hungary's Economic Development and Innovation Operative Programme (GINOP‐2.3.2‐15‐2016‐00051), NKFIH K127961, and the Semmelweis Science and Innovation Fund. MTA-ELTE NAP B Opto-Neuropharmacology Group, Budapest, Hungary Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary School of PhD Studies, Semmelweis University, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Motor Pharmacology Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary Export Date: 26 April 2021 CODEN: BJPCB Correspondence Address: Mike, A.; MTA-ELTE NAP B Opto-Neuropharmacology GroupHungary; email: arpadmike1@gmail.com Correspondence Address: Mike, A.; Plant Protection Institute, Hungary; email: arpadmike1@gmail.com Correspondence Address: Mike, A.; Department of Biochemistry, Hungary; email: arpadmike1@gmail.com Funding details: KTIA‐NAP‐13‐2‐2014‐002 Funding details: GINOP‐2.3.2‐15‐2016‐00051 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH, K127961 Funding text 1: This work was supported by the Hungarian Brain Research Program (KTIA‐NAP‐13‐2‐2014‐002), Hungary's Economic Development and Innovation Operative Programme (GINOP‐2.3.2‐15‐2016‐00051), NKFIH K127961, and the Semmelweis Science and Innovation Fund. AB - Sodium channel inhibitors can be used to treat hyperexcitability-related diseases, including epilepsies, pain syndromes, neuromuscular disorders, and cardiac arrhythmias. The applicability of these drugs is limited by their nonspecific effect on physiological function. They act mainly by sodium channel block and in addition by modulation of channel kinetics. While channel block inhibits healthy and pathological tissue equally, modulation can preferentially inhibit pathological activity. An ideal drug designed to target the sodium channels of pathological tissue would act predominantly by modulation. Thus far, no such drug has been described.Patch-clamp experiments with ultra-fast solution exchange and photolabeling-coupled electrophysiology were applied to describe the unique mechanism of riluzole on Nav1.4 sodium channels. In silico docking experiments were used to study the molecular details of binding.We present evidence that riluzole acts predominantly by non-blocking modulation. We propose that, being a relatively small molecule, riluzole is able to stay bound to the binding site, but nonetheless stay off the conduction pathway, by residing in one of the fenestrations. We demonstrate how this mechanism can be recognized.Our results identify riluzole as the prototype of this new class of sodium channel inhibitors. Drugs of this class are expected to selectively prevent hyperexcitability, while having minimal effect on cells firing at a normal rate from a normal resting potential. LA - English DB - MTMT ER - TY - JOUR AU - Nagy, Tamás AU - Tóth, Á. AU - Telbisz, Ágnes Mária AU - Sarkadi, Balázs AU - Tordai, Hedvig AU - Tordai, Attila AU - Hegedűs, Tamás TI - The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 78 PY - 2021 IS - 5 SP - 2329 EP - 2339 PG - 11 SN - 1420-682X DO - 10.1007/s00018-020-03651-3 UR - https://m2.mtmt.hu/api/publication/31623716 ID - 31623716 AB - 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). LA - English DB - MTMT ER - TY - JOUR AU - Gáspárné Csizmadia, Georgina AU - Farkas, Bianka Vivien AU - Katona, E. AU - Tusnády, Gábor AU - Hegedűs, Tamás TI - Using MemBlob to Analyze Transmembrane Regions Based on Cryo-EM Maps JF - METHODS IN MOLECULAR BIOLOGY J2 - METHODS MOL BIOL VL - 2112 PY - 2020 SP - 123 EP - 130 PG - 8 SN - 1064-3745 DO - 10.1007/978-1-0716-0270-6_9 UR - https://m2.mtmt.hu/api/publication/31177534 ID - 31177534 AB - Transmembrane proteins include membrane channels, pores, and receptors and, as such, comprise an important part of the proteome, yet our knowledge about them is much less complete than about soluble, globular proteins. An important aspect of transmembrane protein structure is their exact position within the lipid bilayer, a feature hard to investigate experimentally at the atomic level. Here we describe MemBlob, a novel approach utilizing difference electron density maps obtained by cryo-EM studies of transmembrane proteins. The idea behind is that the nonprotein part of such maps carries information on the exact localization of the membrane mimetics used in the experiment and can be used to extract the positional information of the protein within the membrane. MemBlob uses a structural model of the protein and an experimental electron density map to provide an estimation of the surface residues interacting with the membrane. LA - English DB - MTMT ER - TY - JOUR AU - Gáspárné Csizmadia, Georgina AU - Erdős, Gábor AU - Tordai, Hedvig AU - Padányi, Rita AU - Tosatto, Silvio AU - Dosztányi, Zsuzsanna AU - Hegedűs, Tamás TI - The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes JF - NUCLEIC ACIDS RESEARCH J2 - NUCLEIC ACIDS RES VL - 49 PY - 2020 IS - D1 SP - D355 EP - D360 SN - 0305-1048 DO - 10.1093/nar/gkaa954 UR - https://m2.mtmt.hu/api/publication/31641470 ID - 31641470 N1 - Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary MTA-ELTE Lendület Bioinformatics Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, 1117, Hungary Department of Biomedical Sciences, University of Padua, Padua, 35131, Italy Cited By :3 Export Date: 31 March 2022 CODEN: NARHA Correspondence Address: Hegedűs, T.; Department of Biophysics and Radiation Biology, Hungary; email: hegedus@hegelab.org LA - English DB - MTMT ER - TY - JOUR AU - Farkas, Bianka Vivien AU - Gáspárné Csizmadia, Georgina AU - Katona, Eszter AU - Tusnády, Gábor AU - Hegedűs, Tamás TI - MemBlob database and server for identifying transmembrane regions using cryo-EM maps JF - BIOINFORMATICS J2 - BIOINFORMATICS VL - 36 PY - 2020 IS - 8 SP - 2595 EP - 2598 PG - 4 SN - 1367-4803 DO - 10.1093/bioinformatics/btz539 UR - https://m2.mtmt.hu/api/publication/30745372 ID - 30745372 N1 - Cited By :2 Export Date: 15 May 2020 Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, 1094, Hungary MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Budapest, 1094, Hungary Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, 1083, Hungary Faculty of Brain Sciences, University College London, London, W1T 7NF, United Kingdom 'Momentum' Membrane Protein Bioinformatics Research Group, Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Budapest, 1117, Hungary Cited By :2 Export Date: 24 July 2020 CODEN: BOINF Correspondence Address: Hegedus, T.; Department of Biophysics and Radiation Biology, Semmelweis UniversityHungary; email: tamas.hegedus@hegelab.org Funding details: HEGEDU18I0 Funding details: K127961, K125607, K119287, K111678 Funding details: Cystic Fibrosis Foundation Funding text 1: This work was supported by the National Research, Development and Innovation Office [K111678, K119287, K125607, K127961], the Cystic Fibrosis Foundation [CFF HEGEDU18I0] and the Semmelweis Science and Innovation Fund. AB - The identification of transmembrane helices in transmembrane proteins is crucial, not only to understand their mechanism of action, but also to develop new therapies. While experimental data on the boundaries of membrane-embedded regions is sparse, this information is present in cryo-electron microscopy (cryo-EM) density maps and it has not been utilized yet for determining membrane regions. We developed a computational pipeline, where the inputs of a cryo-EM map, the corresponding atomistic structure, and the potential bilayer orientation determined by TMDET algorithm of a given protein result in an output defining the residues assigned to the bulk water phase, lipid interface, and the lipid hydrophobic core. Based on this method, we built a database involving published cryo-EM protein structures and a server to be able to compute this data for newly obtained structures.http://memblob.hegelab.org.Supplementary data are available at Bioinformatics online. LA - English DB - MTMT ER -