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Structure paper

TitleStructural basis for activation and potentiation in a human α5β3 GABA receptor.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateJun 15, 2026
AuthorsJohn Cowgill / Chen Fan / Jan Steyaert / Rebecca J Howard / Erik Lindahl /
PubMed AbstractAnesthetics and anticonvulsants act, in part, through diverse populations of type-A ɣ-aminobutyric acid receptors (GABARs) formed from a pool of 19 subunits. In the hippocampus, α5 subunits ...Anesthetics and anticonvulsants act, in part, through diverse populations of type-A ɣ-aminobutyric acid receptors (GABARs) formed from a pool of 19 subunits. In the hippocampus, α5 subunits primarily coassemble with β3 and, in some cases, γ2, generating numerous subtypes with differential functional and pharmacological properties critical in learning and memory. The stoichiometry, structure, and gating of these subpopulations are poorly understood. Here we show using cryogenic electron microscopy and electrophysiology that the human α5β3 GABAR predominantly assembles with 2α:3β stoichiometry, though a minority population of 1α:4β indicates multiple assemblies are possible. In a resting-like state, a conserved activation gate and Zn-coordination at histidines on β3 block ion conduction. Upon GABA binding, global rearrangements release Zn and open the activation gate in nearly all receptors. The activated receptor is unaffected upon binding the anesthetic etomidate or anticonvulsant topiramate, supporting a conformational selection mechanism of action. This work thus reveals the assembly, activation, and modulation of a GABAR subtype critical to cognition, providing templates for structure-based drug discovery.
External linksNat Commun / PubMed:42297817 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.81 Å
Structure data

51980

9haa

EMDB-51980, PDB-9haa:
a5b3 GABAA Receptor resting state
Method: EM (single particle) / Resolution: 3.14 Å

52312

9hnq

EMDB-52312, PDB-9hnq:
a5b3 GABAA Receptor bound to GABA and Mb25 in desensitized state in detergent micelles
Method: EM (single particle) / Resolution: 3.81 Å

52314

9hns

EMDB-52314, PDB-9hns:
a5b3 GABAAR bound to GABA and Mb25 in a desensitized state in saposin nanodiscs after long GABA treatment
Method: EM (single particle) / Resolution: 3.1 Å

52315

9hnt

EMDB-52315, PDB-9hnt:
a5b3 GABAAR bound to Etomidate, GABA, and Mb25 in a desensitized state in saposin nanodiscs
Method: EM (single particle) / Resolution: 3.32 Å

52416

9hum

EMDB-52416, PDB-9hum:
a5b3 GABAAR bound to GABA and Mb25 in a desensitized state in saposin nanodiscs after short GABA treatment
Method: EM (single particle) / Resolution: 3.35 Å

54031

9rl5

EMDB-54031, PDB-9rl5:
a5b3 GABAAR bound to Topiramate, GABA, and Mb25 in a desensitized state in saposin nanodiscs
Method: EM (single particle) / Resolution: 3.1 Å

54151

9rpb

EMDB-54151, PDB-9rpb:
a5b3 GABAAR bound to GABA, and Mb25 in a desensitized state in saposin nanodiscs, topiramate-free
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-BUA:
butanoic acid

ChemComp-EPE:
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / pH buffer*YM

ChemComp-ZN:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM

ChemComp-V8D:
Etomidate

ChemComp-TOR:
[(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-3a-yl]methyl sulfamate

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
  • aequorea victoria (jellyfish)
KeywordsMEMBRANE PROTEIN / GABA receptor / pentameric ligand gated ion channel / cys-loop receptor / GABAA receptor / ion channel / anticonvulsant / a5 GABA receptor

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