Orthosteric and benzodiazepine cavities of the α1β2γ2 GABAA receptor: insights from experimentally validated in silico methods
| Autor: | Juan Francisco Viso, Fernando Zamarreño, Alejandro Giorgetti, María Julia Amundarain, Marcelo Daniel Costabel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
GABAARs – Gamma-Aminobutyric Acid type A receptors
TMD – Transmembrane domain medicine.drug_class i-BZDs – Imidazo-Benzodiazepines Ciencias Físicas In silico 030303 biophysics Central nervous system Presynaptic inhibition ECD – Extracellular domain HOMOLOGY MODELLING purl.org/becyt/ford/1 [https] 03 medical and health sciences BENZODIAZEPINES Structural Biology medicine DOCKING Receptor benzodiazepines Molecular Biology BZDs – Benzodiazepines homology modelling 0303 health sciences Benzodiazepine GABA – Gamma-Aminobutyric acid GABAAR Chemistry GABAA receptor musculoskeletal neural and ocular physiology AChBP – Acetylcholine Binding Protein MD – Molecular Dynamics CNS – Central Nervous System GLIC – Gloeobacter ligand-gated ion channel purl.org/becyt/ford/1.3 [https] General Medicine ELIC – Erwinia ligand-gated ion channel molecular dynamics GABA - Gamma-aminobutyric acid SCAM – Substituted cysteine accessibility method medicine.anatomical_structure nervous system Docking (molecular) docking Biophysics POPC – 1-palmitoyl-2-oleoyl-phophatidylcholine MOLECULAR DYNAMICS CIENCIAS NATURALES Y EXACTAS Física de los Materiales Condensados |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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