Dataset Information

Cryo-EM movies of the human α1β3γ2 GABA_A receptor in a lipid bilayer bound to diazepam and GABA

ABSTRACT:

SUBMITTER: Alexandru Radu Aricescu

PROVIDER: EMPIAR-11295 | biostudies-other |

REPOSITORIES: biostudies-other

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Publications

GABAA receptor signalling mechanisms revealed by structural pharmacology.

Masiulis Simonas S Desai Rooma R Uchański Tomasz T Serna Martin Itziar I Laverty Duncan D Karia Dimple D Malinauskas Tomas T Zivanov Jasenko J Pardon Els E Kotecha Abhay A Steyaert Jan J Miller Keith W KW Aricescu A Radu AR

Nature 20190102 7740

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structu ...[more]

PMID: 30602790

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Project description:Type A γ-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABAA receptors5. The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1-β3 triple knockout neurons6. So far, efforts to generate accurate structural models for heteromeric GABAA receptors have been hampered by the use of engineered receptors and the presence of detergents7-9. Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor10,11, the large body of structural work on homologous homopentameric receptor variants12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L-a major synaptic GABAA receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABAA receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABAA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

Dataset Information

Cryo-EM movies of the human α1β3γ2 GABA_A receptor in a lipid bilayer bound to diazepam and GABA

Publications

GABA<sub>A</sub> receptor signalling mechanisms revealed by structural pharmacology.

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Dataset Information

Cryo-EM movies of the human α1β3γ2 GABAA receptor in a lipid bilayer bound to diazepam and GABA

Publications

GABA<sub>A</sub> receptor signalling mechanisms revealed by structural pharmacology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cryo-EM movies of the human α1β3γ2 GABA_A receptor in a lipid bilayer bound to diazepam and GABA