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Abstract:

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.

Registro:

Documento: Artículo
Título:Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor
Autor:Alvarez, L.D.; Estrin, D.A.
Filiación:Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, Ciudad de Buenos Aires, C1428EGA, Argentina
Dpto. Química Inorgánica Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, Ciudad de Buenos Aires, C1428EGA, Argentina
Palabras clave: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
Año:2015
Volumen:154
Página de inicio:159
Página de fin:167
DOI: http://dx.doi.org/10.1016/j.jsbmb.2015.07.012
Título revista:Journal of Steroid Biochemistry and Molecular Biology
Título revista abreviado:J. Steroid Biochem. Mol. Biol.
ISSN:09600760
CODEN:JSBBE
CAS:eltanolone, 128-20-1; protein, 67254-75-5; Neurotransmitter Agents; Receptors, GABA-A
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v154_n_p159_Alvarez

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Citas:

---------- APA ----------
Alvarez, L.D. & Estrin, D.A. (2015) . Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor. Journal of Steroid Biochemistry and Molecular Biology, 154, 159-167.
http://dx.doi.org/10.1016/j.jsbmb.2015.07.012
---------- CHICAGO ----------
Alvarez, L.D., Estrin, D.A. "Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor" . Journal of Steroid Biochemistry and Molecular Biology 154 (2015) : 159-167.
http://dx.doi.org/10.1016/j.jsbmb.2015.07.012
---------- MLA ----------
Alvarez, L.D., Estrin, D.A. "Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor" . Journal of Steroid Biochemistry and Molecular Biology, vol. 154, 2015, pp. 159-167.
http://dx.doi.org/10.1016/j.jsbmb.2015.07.012
---------- VANCOUVER ----------
Alvarez, L.D., Estrin, D.A. Exploring the molecular basis of neurosteroid binding to the β3 homopentameric GABAA receptor. J. Steroid Biochem. Mol. Biol. 2015;154:159-167.
http://dx.doi.org/10.1016/j.jsbmb.2015.07.012