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Structure and dynamics of neurosteroid binding to the α1ß2γ2 GABAA receptor.
Alvarez, Lautaro D; Pecci, Adali.
Afiliación
  • Alvarez LD; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, UMYMFOR, Buenos Aires, Argentina. Electronic address: lalvarez@qo.fcen.uba.ar.
  • Pecci A; Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, IFIBYNE, Buenos Aires, Argentina.
J Steroid Biochem Mol Biol ; 182: 72-80, 2018 09.
Article en En | MEDLINE | ID: mdl-29705269
Neurosteroids are the principal endogenous modulators of the γ-Aminobutyric acid receptors (GABAARs), pentameric membrane-bound proteins that can be assembled from at least 19 subunits. In the most abundant GABAAR arrangement (α1ß2γ2), neurosteroids can potentiate the GABA action as well as produce a direct activation of the channel. The recent crystal structures of neurosteroids bound to α homopentameric GABAAR reveal binding to five equivalent sites. However, these results have been obtained using receptors that are not physiologically relevant, suggesting a need to investigate neurosteroid binding to heteropentameric receptors that exist in the central nervous system. In a previous work, we predicted the neurosteroid binding site by applying molecular modeling methods on the ß3 homopentamer. Here we construct a homology model of the transmembrane domain of the heteropentameric α1ß2γ2 receptor and then, by combining docking and molecular dynamics simulations, we analyzed neurosteroid binding. Results show that the five neurosteroid cavities are conserved in the α1ß2γ2 receptor and all of them are able to bind neurosteroids. Two different binding modes were detected depending on the identity of the residue at position 241 in the transmembrane helix 1. These theoretical findings provide microscopic insights into neurosteroid binding at the heteropentameric GABAAR. The existence of two classes of sites may be associated with how neurosteroids modulate GABAAR. Our finding would represent the essential first step to reach a comprehensive understanding of how these endogenous molecules regulate the central nervous system.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pregnanolona / Conformación Proteica / Receptores de GABA-A Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Steroid Biochem Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pregnanolona / Conformación Proteica / Receptores de GABA-A Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Steroid Biochem Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2018 Tipo del documento: Article Pais de publicación: Reino Unido