Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor
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 (α1β2γ2), neurosteroids can potentiate the GABA action as well as produce...
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2018
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v182_n_p72_Alvarez http://hdl.handle.net/20.500.12110/paper_09600760_v182_n_p72_Alvarez |
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paper:paper_09600760_v182_n_p72_Alvarez2023-06-08T15:57:22Z Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor Activation Binding sites Docking, molecular dynamics simulation GABAA receptors Neurosteroids Potentiation α1β2γ2 heteropentamer 4 aminobutyric acid A receptor alpha1 4 aminobutyric acid A receptor beta2 4 aminobutyric acid A receptor gamma2 brexanolone eltanolone neurosteroid Article binding affinity molecular docking molecular dynamics structural homology 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 (α1β2γ2), 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 β3 homopentamer. Here we construct a homology model of the transmembrane domain of the heteropentameric α1β2γ2 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 α1β2γ2 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. © 2018 Elsevier Ltd 2018 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v182_n_p72_Alvarez http://hdl.handle.net/20.500.12110/paper_09600760_v182_n_p72_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 |
Activation Binding sites Docking, molecular dynamics simulation GABAA receptors Neurosteroids Potentiation α1β2γ2 heteropentamer 4 aminobutyric acid A receptor alpha1 4 aminobutyric acid A receptor beta2 4 aminobutyric acid A receptor gamma2 brexanolone eltanolone neurosteroid Article binding affinity molecular docking molecular dynamics structural homology |
| spellingShingle |
Activation Binding sites Docking, molecular dynamics simulation GABAA receptors Neurosteroids Potentiation α1β2γ2 heteropentamer 4 aminobutyric acid A receptor alpha1 4 aminobutyric acid A receptor beta2 4 aminobutyric acid A receptor gamma2 brexanolone eltanolone neurosteroid Article binding affinity molecular docking molecular dynamics structural homology Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| topic_facet |
Activation Binding sites Docking, molecular dynamics simulation GABAA receptors Neurosteroids Potentiation α1β2γ2 heteropentamer 4 aminobutyric acid A receptor alpha1 4 aminobutyric acid A receptor beta2 4 aminobutyric acid A receptor gamma2 brexanolone eltanolone neurosteroid Article binding affinity molecular docking molecular dynamics structural homology |
| description |
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 (α1β2γ2), 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 β3 homopentamer. Here we construct a homology model of the transmembrane domain of the heteropentameric α1β2γ2 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 α1β2γ2 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. © 2018 Elsevier Ltd |
| title |
Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| title_short |
Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| title_full |
Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| title_fullStr |
Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| title_full_unstemmed |
Structure and dynamics of neurosteroid binding to the α1β2γ2 GABAA receptor |
| title_sort |
structure and dynamics of neurosteroid binding to the α1β2γ2 gabaa receptor |
| publishDate |
2018 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_09600760_v182_n_p72_Alvarez http://hdl.handle.net/20.500.12110/paper_09600760_v182_n_p72_Alvarez |
| _version_ |
1768545746981748736 |