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

Duncan Laverty, Rooma Desai, Tomasz Uchanski, Simonas Masiulis, Wojciech J Stec, Tomas Malinauskas, Jasenko Zivanov, Els Pardon, Jan Steyaert, Keith W Miller, A Radu Aricescu

Research output: Contribution to journalArticle

152 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)516-520
Number of pages5
Issue number7740
Early online date2 Jan 2019
Publication statusPublished - 24 Jan 2019


  • Allosteric Regulation
  • Amino Acid Sequence
  • Binding Sites
  • Cryoelectron Microscopy
  • Electric Conductivity
  • Humans
  • Lipid Bilayers/chemistry
  • Models, Molecular
  • Molecular Docking Simulation
  • Nanostructures/chemistry
  • Phosphatidylinositol 4,5-Diphosphate/chemistry
  • Protein Isoforms/chemistry
  • Protein Structure, Quaternary
  • Receptors, GABA-A/chemistry


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