Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods
- Autores
- Amundarain, María Julia; Viso, Juan Francisco; Zamarreño, Fernando; Giorgetti, Alejandro; Costabel, Marcelo Daniel
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- γ-aminobutyric acid-type A (GABA A ) receptors mediate fast synaptic inhibition in the central nervous system of mammals. They are modulated via several sites by numerous compounds, which include GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Due to their potential as targets of novel drugs, a detailed knowledge of their structure–function relationships is needed. Here, we present the model of the α 1 β 2 γ 2 subtype GABA A receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. The model is based on the crystallographic structure of the human β 3 homopentamer GABA A receptor. The complexes were refined using atomistic molecular dynamics simulations. This allowed a broad description of the binding modes and the detection of important interactions in agreement with experimental information. From the best of our knowledge, this is the only model of the α 1 β 2 γ 2 GABA A receptor that represents altogether the desensitized state of the channel and comprehensively describes the interactions of ligands of the orthosteric and benzodiazepines binding sites in agreement with the available experimental data. Furthermore, it is able to explain small differences regarding the binding of a variety of chemically divergent ligands. Finally, this new model may pave the way for the design of focused experimental studies that will allow a deeper description of the receptor.
Fil: Amundarain, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Viso, Juan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Zamarreño, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina
Fil: Giorgetti, Alejandro. Universita di Verona; Italia. Forschungszentrum Jülich; Alemania
Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina - Materia
-
BENZODIAZEPINES
DOCKING
GABAAR
HOMOLOGY MODELLING
MOLECULAR DYNAMICS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/91985
Ver los metadatos del registro completo
| id |
CONICETDig_408620b26771e36c2b7f1102c8d936a9 |
|---|---|
| oai_identifier_str |
oai:ri.conicet.gov.ar:11336/91985 |
| network_acronym_str |
CONICETDig |
| repository_id_str |
3498 |
| network_name_str |
CONICET Digital (CONICET) |
| spelling |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methodsAmundarain, María JuliaViso, Juan FranciscoZamarreño, FernandoGiorgetti, AlejandroCostabel, Marcelo DanielBENZODIAZEPINESDOCKINGGABAARHOMOLOGY MODELLINGMOLECULAR DYNAMICShttps://purl.org/becyt/ford/1.3https://purl.org/becyt/ford/1γ-aminobutyric acid-type A (GABA A ) receptors mediate fast synaptic inhibition in the central nervous system of mammals. They are modulated via several sites by numerous compounds, which include GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Due to their potential as targets of novel drugs, a detailed knowledge of their structure–function relationships is needed. Here, we present the model of the α 1 β 2 γ 2 subtype GABA A receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. The model is based on the crystallographic structure of the human β 3 homopentamer GABA A receptor. The complexes were refined using atomistic molecular dynamics simulations. This allowed a broad description of the binding modes and the detection of important interactions in agreement with experimental information. From the best of our knowledge, this is the only model of the α 1 β 2 γ 2 GABA A receptor that represents altogether the desensitized state of the channel and comprehensively describes the interactions of ligands of the orthosteric and benzodiazepines binding sites in agreement with the available experimental data. Furthermore, it is able to explain small differences regarding the binding of a variety of chemically divergent ligands. Finally, this new model may pave the way for the design of focused experimental studies that will allow a deeper description of the receptor.Fil: Amundarain, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Viso, Juan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Zamarreño, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaFil: Giorgetti, Alejandro. Universita di Verona; Italia. Forschungszentrum Jülich; AlemaniaFil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; ArgentinaAdenine Press2019-05-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/91985Amundarain, María Julia; Viso, Juan Francisco; Zamarreño, Fernando; Giorgetti, Alejandro; Costabel, Marcelo Daniel; Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods; Adenine Press; Journal Of Biomolecular Structure & Dynamics; 37; 6; 04-5-2019; 1597-16150739-1102CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1080/07391102.2018.1462733info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.1080/07391102.2018.1462733info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T12:13:34Zoai:ri.conicet.gov.ar:11336/91985instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-29 12:13:35.077CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| title |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| spellingShingle |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods Amundarain, María Julia BENZODIAZEPINES DOCKING GABAAR HOMOLOGY MODELLING MOLECULAR DYNAMICS |
| title_short |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| title_full |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| title_fullStr |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| title_full_unstemmed |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| title_sort |
Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods |
| dc.creator.none.fl_str_mv |
Amundarain, María Julia Viso, Juan Francisco Zamarreño, Fernando Giorgetti, Alejandro Costabel, Marcelo Daniel |
| author |
Amundarain, María Julia |
| author_facet |
Amundarain, María Julia Viso, Juan Francisco Zamarreño, Fernando Giorgetti, Alejandro Costabel, Marcelo Daniel |
| author_role |
author |
| author2 |
Viso, Juan Francisco Zamarreño, Fernando Giorgetti, Alejandro Costabel, Marcelo Daniel |
| author2_role |
author author author author |
| dc.subject.none.fl_str_mv |
BENZODIAZEPINES DOCKING GABAAR HOMOLOGY MODELLING MOLECULAR DYNAMICS |
| topic |
BENZODIAZEPINES DOCKING GABAAR HOMOLOGY MODELLING MOLECULAR DYNAMICS |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.3 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
γ-aminobutyric acid-type A (GABA A ) receptors mediate fast synaptic inhibition in the central nervous system of mammals. They are modulated via several sites by numerous compounds, which include GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Due to their potential as targets of novel drugs, a detailed knowledge of their structure–function relationships is needed. Here, we present the model of the α 1 β 2 γ 2 subtype GABA A receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. The model is based on the crystallographic structure of the human β 3 homopentamer GABA A receptor. The complexes were refined using atomistic molecular dynamics simulations. This allowed a broad description of the binding modes and the detection of important interactions in agreement with experimental information. From the best of our knowledge, this is the only model of the α 1 β 2 γ 2 GABA A receptor that represents altogether the desensitized state of the channel and comprehensively describes the interactions of ligands of the orthosteric and benzodiazepines binding sites in agreement with the available experimental data. Furthermore, it is able to explain small differences regarding the binding of a variety of chemically divergent ligands. Finally, this new model may pave the way for the design of focused experimental studies that will allow a deeper description of the receptor. Fil: Amundarain, María Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina Fil: Viso, Juan Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina Fil: Zamarreño, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina Fil: Giorgetti, Alejandro. Universita di Verona; Italia. Forschungszentrum Jülich; Alemania Fil: Costabel, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Física del Sur. Universidad Nacional del Sur. Departamento de Física. Instituto de Física del Sur; Argentina |
| description |
γ-aminobutyric acid-type A (GABA A ) receptors mediate fast synaptic inhibition in the central nervous system of mammals. They are modulated via several sites by numerous compounds, which include GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Due to their potential as targets of novel drugs, a detailed knowledge of their structure–function relationships is needed. Here, we present the model of the α 1 β 2 γ 2 subtype GABA A receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. The model is based on the crystallographic structure of the human β 3 homopentamer GABA A receptor. The complexes were refined using atomistic molecular dynamics simulations. This allowed a broad description of the binding modes and the detection of important interactions in agreement with experimental information. From the best of our knowledge, this is the only model of the α 1 β 2 γ 2 GABA A receptor that represents altogether the desensitized state of the channel and comprehensively describes the interactions of ligands of the orthosteric and benzodiazepines binding sites in agreement with the available experimental data. Furthermore, it is able to explain small differences regarding the binding of a variety of chemically divergent ligands. Finally, this new model may pave the way for the design of focused experimental studies that will allow a deeper description of the receptor. |
| publishDate |
2019 |
| dc.date.none.fl_str_mv |
2019-05-04 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/91985 Amundarain, María Julia; Viso, Juan Francisco; Zamarreño, Fernando; Giorgetti, Alejandro; Costabel, Marcelo Daniel; Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods; Adenine Press; Journal Of Biomolecular Structure & Dynamics; 37; 6; 04-5-2019; 1597-1615 0739-1102 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/91985 |
| identifier_str_mv |
Amundarain, María Julia; Viso, Juan Francisco; Zamarreño, Fernando; Giorgetti, Alejandro; Costabel, Marcelo Daniel; Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods; Adenine Press; Journal Of Biomolecular Structure & Dynamics; 37; 6; 04-5-2019; 1597-1615 0739-1102 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1080/07391102.2018.1462733 info:eu-repo/semantics/altIdentifier/url/https://www.tandfonline.com/doi/full/10.1080/07391102.2018.1462733 |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
| eu_rights_str_mv |
openAccess |
| rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
| dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Adenine Press |
| publisher.none.fl_str_mv |
Adenine Press |
| dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
| reponame_str |
CONICET Digital (CONICET) |
| collection |
CONICET Digital (CONICET) |
| instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
| repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
| _version_ |
1847426983993016320 |
| score |
13.10058 |