Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor

Neurosteroids are the principal endogenous modulators of GABAA receptors (GABAARs), which are pentameric membrane-bound proteins that regulate the passage of chloride ions from the extracellular to the intracellular compartment. As consequence of their ability to modify inhibitory functions in the b...

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Autores principales:	Alvarez, L.D., Estrin, D.A.
Formato:	JOUR
Materias:	Binding site GABAA receptor Neurosteroids Specific recognition β3 homopentamers 3alpha hydroxy 5alpha pregnan 20 one 4 aminobutyric acid A receptor beta3 homopentameric 4 aminobutyric acid A receptor eltanolone neurosteroid protein transmembrane domain 1 protein transmembrane domain 3 protein transmembrane domain 4 protein unclassified drug agents interacting with transmitter, hormone or drug receptors protein binding algorithm Article binding affinity binding site crystal structure human mathematical analysis mathematical computing molecular biology molecular docking molecular dynamics molecular interaction physiological process protein analysis structure activity relation chemistry metabolism Molecular Dynamics Simulation Neurotransmitter Agents Protein Binding Receptors, GABA-A
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_09600760_v154_n_p159_Alvarez
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_09600760_v154_n_p159_Alvarez
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spelling	todo:paper_09600760_v154_n_p159_Alvarez2023-10-03T15:53:24Z Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor Alvarez, L.D. Estrin, D.A. Binding site GABAA receptor Neurosteroids Specific recognition β3 homopentamers 3alpha hydroxy 5alpha pregnan 20 one 4 aminobutyric acid A receptor beta3 homopentameric 4 aminobutyric acid A receptor eltanolone neurosteroid protein transmembrane domain 1 protein transmembrane domain 3 protein transmembrane domain 4 protein unclassified drug 4 aminobutyric acid A receptor agents interacting with transmitter, hormone or drug receptors protein binding algorithm Article binding affinity binding site crystal structure human mathematical analysis mathematical computing molecular biology molecular docking molecular dynamics molecular interaction physiological process protein analysis structure activity relation chemistry metabolism Molecular Dynamics Simulation Neurotransmitter Agents Protein Binding Receptors, GABA-A Neurosteroids are the principal endogenous modulators of GABAA receptors (GABAARs), which are pentameric membrane-bound proteins that regulate the passage of chloride ions from the extracellular to the intracellular compartment. As consequence of their ability to modify inhibitory functions in the brain, neurosteroids have high physiological and clinical importance and may act as anesthetic, anticonvulsant and anxiolytic drugs. Despite their relevance, essential issues regarding neurosteroid action on GABAARs are still unsettled. In particular, residues taking part of the steroid recognition are not definitely identified. Taking as starting point the first reported crystal structure of a human GABAA receptor (a β3 homopentamer), we have explored through a combination of computational methods (a cavity-detection algorithm, docking and molecular dynamics simulations) the binding mode of two structurally different representative neurosteroids, pregnanolone and allopregnanolone. We have identified a neurosteroid binding site between the TM3 of one subunit and TM1 and TM4 of the adjacent subunit that is consistent with the set of experimental data reported for the action of neurosteroids on β3 homopentamers. These sites are able to properly accommodate both overall torsioned and flat steroidal structures and they specifically recognize the 3-OH group, explaining the requirement of a 3α-configuration for the activity. We believe that this work provides for first time convincing information about the molecular interaction between neurosteroids and a GABAAR. This information largely increases our understanding of this fundamental ligand-receptor system. © 2015 Elsevier Ltd. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09600760_v154_n_p159_Alvarez
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Binding site GABAA receptor Neurosteroids Specific recognition β3 homopentamers 3alpha hydroxy 5alpha pregnan 20 one 4 aminobutyric acid A receptor beta3 homopentameric 4 aminobutyric acid A receptor eltanolone neurosteroid protein transmembrane domain 1 protein transmembrane domain 3 protein transmembrane domain 4 protein unclassified drug 4 aminobutyric acid A receptor agents interacting with transmitter, hormone or drug receptors protein binding algorithm Article binding affinity binding site crystal structure human mathematical analysis mathematical computing molecular biology molecular docking molecular dynamics molecular interaction physiological process protein analysis structure activity relation chemistry metabolism Molecular Dynamics Simulation Neurotransmitter Agents Protein Binding Receptors, GABA-A
spellingShingle	Binding site GABAA receptor Neurosteroids Specific recognition β3 homopentamers 3alpha hydroxy 5alpha pregnan 20 one 4 aminobutyric acid A receptor beta3 homopentameric 4 aminobutyric acid A receptor eltanolone neurosteroid protein transmembrane domain 1 protein transmembrane domain 3 protein transmembrane domain 4 protein unclassified drug 4 aminobutyric acid A receptor agents interacting with transmitter, hormone or drug receptors protein binding algorithm Article binding affinity binding site crystal structure human mathematical analysis mathematical computing molecular biology molecular docking molecular dynamics molecular interaction physiological process protein analysis structure activity relation chemistry metabolism Molecular Dynamics Simulation Neurotransmitter Agents Protein Binding Receptors, GABA-A Alvarez, L.D. Estrin, D.A. Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
topic_facet	Binding site GABAA receptor Neurosteroids Specific recognition β3 homopentamers 3alpha hydroxy 5alpha pregnan 20 one 4 aminobutyric acid A receptor beta3 homopentameric 4 aminobutyric acid A receptor eltanolone neurosteroid protein transmembrane domain 1 protein transmembrane domain 3 protein transmembrane domain 4 protein unclassified drug 4 aminobutyric acid A receptor agents interacting with transmitter, hormone or drug receptors protein binding algorithm Article binding affinity binding site crystal structure human mathematical analysis mathematical computing molecular biology molecular docking molecular dynamics molecular interaction physiological process protein analysis structure activity relation chemistry metabolism Molecular Dynamics Simulation Neurotransmitter Agents Protein Binding Receptors, GABA-A
description	Neurosteroids are the principal endogenous modulators of GABAA receptors (GABAARs), which are pentameric membrane-bound proteins that regulate the passage of chloride ions from the extracellular to the intracellular compartment. As consequence of their ability to modify inhibitory functions in the brain, neurosteroids have high physiological and clinical importance and may act as anesthetic, anticonvulsant and anxiolytic drugs. Despite their relevance, essential issues regarding neurosteroid action on GABAARs are still unsettled. In particular, residues taking part of the steroid recognition are not definitely identified. Taking as starting point the first reported crystal structure of a human GABAA receptor (a β3 homopentamer), we have explored through a combination of computational methods (a cavity-detection algorithm, docking and molecular dynamics simulations) the binding mode of two structurally different representative neurosteroids, pregnanolone and allopregnanolone. We have identified a neurosteroid binding site between the TM3 of one subunit and TM1 and TM4 of the adjacent subunit that is consistent with the set of experimental data reported for the action of neurosteroids on β3 homopentamers. These sites are able to properly accommodate both overall torsioned and flat steroidal structures and they specifically recognize the 3-OH group, explaining the requirement of a 3α-configuration for the activity. We believe that this work provides for first time convincing information about the molecular interaction between neurosteroids and a GABAAR. This information largely increases our understanding of this fundamental ligand-receptor system. © 2015 Elsevier Ltd.
format	JOUR
author	Alvarez, L.D. Estrin, D.A.
author_facet	Alvarez, L.D. Estrin, D.A.
author_sort	Alvarez, L.D.
title	Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
title_short	Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
title_full	Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
title_fullStr	Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
title_full_unstemmed	Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
title_sort	exploring the molecular basis of neurosteroid binding to the β3 homopentameric gabaa receptor
url	http://hdl.handle.net/20.500.12110/paper_09600760_v154_n_p159_Alvarez
work_keys_str_mv	AT alvarezld exploringthemolecularbasisofneurosteroidbindingtotheb3homopentamericgabaareceptor AT estrinda exploringthemolecularbasisofneurosteroidbindingtotheb3homopentamericgabaareceptor
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Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor

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