@article{MTMT:31821613,
	author = {Földi, Mátyás Csaba and Pesti, Krisztina and Zboray, Katalin and Toth, Adam V and Hegedűs, Tamás and Málnási Csizmadia, András and Lukács, Péter and Mike, Árpád},
	doi = {10.1111/bph.15365},
	title = {The mechanism of non-blocking inhibition of sodium channels revealed by conformation-selective photolabeling},
	journal-iso = {BR J PHARMACOL},
	journal = {BRITISH JOURNAL OF PHARMACOLOGY},
	volume = {178},
	unique-id = {31821613},
	issn = {0007-1188},
	abstract = {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.},
	keywords = {EPILEPSY; PAIN; BINDING SITES; Sodium Channels; ARRHYTHMIAS; riluzole; local anesthetics},
	year = {2021},
	eissn = {1476-5381},
	pages = {1200-1217},
	orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629; Málnási Csizmadia, András/0000-0002-2430-8398; Mike, Árpád/0000-0002-9095-8161}
}

@article{MTMT:31623716,
	author = {Nagy, T. and Tóth, Á. and Telbisz, Ágnes Mária and Sarkadi, Balázs and Tordai, Hedvig and Tordai, Attila and Hegedűs, Tamás},
	doi = {10.1007/s00018-020-03651-3},
	title = {The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations},
	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 = {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}
}

@{MTMT:31177534,
	author = {Gáspárné Csizmadia, Georgina and Farkas, Bianka Vivien and Katona, E. and Tusnády, Gábor and Hegedűs, Tamás},
	booktitle = {Structural Bioinformatics},
	doi = {10.1007/978-1-0716-0270-6_9},
	title = {Using MemBlob to Analyze Transmembrane Regions Based on Cryo-EM Maps},
	unique-id = {31177534},
	abstract = {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.},
	keywords = {transmembrane region; Cryo-EM map; Lipid interface},
	year = {2020},
	pages = {123-130},
	orcid-numbers = {Gáspárné Csizmadia, Georgina/0000-0003-4321-9670; Farkas, Bianka Vivien/0000-0002-0258-6864; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:31641470,
	author = {Gáspárné Csizmadia, Georgina and Erdős, Gábor and Tordai, Hedvig and Padányi, Rita and Tosatto, Silvio and Dosztányi, Zsuzsanna and Hegedűs, Tamás},
	doi = {10.1093/nar/gkaa954},
	title = {The MemMoRF database for recognizing disordered protein regions interacting with cellular membranes},
	journal-iso = {NUCLEIC ACIDS RES},
	journal = {NUCLEIC ACIDS RESEARCH},
	volume = {49},
	unique-id = {31641470},
	issn = {0305-1048},
	year = {2020},
	eissn = {1362-4962},
	pages = {D355-D360},
	orcid-numbers = {Gáspárné Csizmadia, Georgina/0000-0003-4321-9670; Tordai, Hedvig/0000-0002-0875-5569; Padányi, Rita/0000-0001-7798-0463; Dosztányi, Zsuzsanna/0000-0002-3624-5937; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:30745372,
	author = {Farkas, Bianka Vivien and Gáspárné Csizmadia, Georgina and Katona, Eszter and Tusnády, Gábor and Hegedűs, Tamás},
	doi = {10.1093/bioinformatics/btz539},
	title = {MemBlob database and server for identifying transmembrane regions using cryo-EM maps},
	journal-iso = {BIOINFORMATICS},
	journal = {BIOINFORMATICS},
	volume = {36},
	unique-id = {30745372},
	issn = {1367-4803},
	abstract = {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.},
	year = {2020},
	eissn = {1460-2059},
	pages = {2595-2598},
	orcid-numbers = {Farkas, Bianka Vivien/0000-0002-0258-6864; Gáspárné Csizmadia, Georgina/0000-0003-4321-9670; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT: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},
	title = {Discovering the chloride pathway in the CFTR channel},
	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:31642729,
	author = {Geisler, Markus and Hegedűs, Tamás},
	doi = {10.1002/1873-3468.13983},
	title = {A twist in the ABC: Regulation of ABC transporter trafficking and transport by FK506-binding proteins},
	journal-iso = {FEBS LETT},
	journal = {FEBS LETTERS},
	volume = {594},
	unique-id = {31642729},
	issn = {0014-5793},
	year = {2020},
	eissn = {1873-3468},
	pages = {3986-4000},
	orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:31634543,
	author = {Sarkadi, Balázs and Homolya, László and Hegedűs, Tamás},
	doi = {10.1002/1873-3468.13947},
	title = {The ABCG2/BCRP transporter and its variants - from structure to pathology},
	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}
}

@{MTMT:30623774,
	author = {Gáspárné Csizmadia, Georgina and Farkas, Bianka and Katona, Eszter and E. Tusnády, Gábor and Hegedűs, Tamás},
	booktitle = {Porgramme and Books of abstracts - Hungarian Molecular Life Sciences 2019},
	title = {Defining transmembrane regions using cryo-EM maps: the MemBlob database and server},
	unique-id = {30623774},
	year = {2019},
	pages = {92},
	orcid-numbers = {Gáspárné Csizmadia, Georgina/0000-0003-4321-9670; Hegedűs, Tamás/0000-0002-0331-9629}
}

@article{MTMT:30654928,
	author = {Lengyel, Miklós and Erdélyi, Ferenc and Pergel, Enikő and Polonkáné Bálint, Ágnes and Dobolyi, Alice and Bozsaki, Peter and Dux, Mária and Király, Kornél P and Hegedűs, Tamás and Czirják, Gábor and Mátyus, Péter and Enyedi, Péter},
	doi = {10.1124/mol.118.115626},
	title = {Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel},
	journal-iso = {MOL PHARMACOL},
	journal = {MOLECULAR PHARMACOLOGY},
	volume = {95},
	unique-id = {30654928},
	issn = {0026-895X},
	abstract = {Cloxyquin has been reported as a specific activator of TRESK (K2P18.1, TWIK-related spinal cord K+ channel) background potassium channel. In this study, we have synthetized chemically modified analogues of cloxyquin and tested their effects on TRESK and other K2P channels. The currents of murine K2P channels, expressed heterologously in Xenopus oocytes, were measured by two-electrode voltage clamp, whereas the native background K+ conductance of mouse dorsal root ganglion (DRG) neurons was examined by the whole-cell patch clamp method. Some of the analogues retained the activator character of the parent compound, but more interestingly, other derivatives inhibited mouse TRESK current. The inhibitor analogues (A2764 and A2793) exerted state-dependent effect. The degree of inhibition by 100 µM A2764 (77.8±1.5%, n=6) was larger in the activated state of TRESK (i.e. after calcineurin-dependent stimulation) than in the resting state of the channel (42.8±4.3% inhibition, n=7). The selectivity of the inhibitor compounds was tested on several K2P channels. A2793 inhibited TASK-1 (100 µM, 53.4±6%, n=5), while A2764 was more selective for TRESK, it only moderately influenced TREK-1 and TALK-1. The effect of A2764 was also examined on the background K+ currents of DRG neurons. A subpopulation of DRG neurons, prepared from wild-type animals, expressed background K+ currents sensitive to A2764, while the inhibitor did not affect the currents in the DRG neurons of TRESK-deficient mice. Accordingly, A2764 may prove to be useful for the identification of TRESK current in native cells, and for the investigation of the role of the channel in nociception and migraine.},
	keywords = {POTASSIUM CHANNELS; PAIN; ION CHANNELS; Electrophysiology},
	year = {2019},
	eissn = {1521-0111},
	pages = {652-660},
	orcid-numbers = {Lengyel, Miklós/0000-0001-6382-6369; Dux, Mária/0000-0002-9941-8188; Király, Kornél P/0000-0002-7252-0422; Hegedűs, Tamás/0000-0002-0331-9629; Czirják, Gábor/0000-0002-5485-2327; Mátyus, Péter/0000-0003-3963-9445; Enyedi, Péter/0000-0001-9541-0712}
}