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Cryo-EM movies of the human α1β3γ2 GABA_A receptor in a lipid bilayer

ABSTRACT:

SUBMITTER: Alexandru Radu Aricescu

PROVIDER: EMPIAR-11255 | biostudies-other |

REPOSITORIES: biostudies-other

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Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer.

Laverty Duncan D Desai Rooma R Uchański Tomasz T Masiulis Simonas S Stec Wojciech J WJ Malinauskas Tomas T Zivanov Jasenko J Pardon Els E Steyaert Jan J Miller Keith W KW Aricescu A Radu AR

Nature 20190102 7740

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 subu ...[more]

PMID: 30602789

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Project description:Type A ?-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 ?1?2/3?2 GABAA receptors5. The ?3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in ?1-?3 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 ?1?3?2L-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 ?1 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

Publications

Cryo-EM structure of the human α1β3γ2 GABA<sub>A</sub> receptor in a lipid bilayer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Dataset Information

Cryo-EM movies of the human α1β3γ2 GABAA receptor in a lipid bilayer

Publications

Cryo-EM structure of the human α1β3γ2 GABA<sub>A</sub> receptor in a lipid bilayer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Cryo-EM movies of the human α1β3γ2 GABA_A receptor in a lipid bilayer