9RPB
a5b3 GABAAR bound to GABA, and Mb25 in a desensitized state in saposin nanodiscs, topiramate-free
Summary for 9RPB
| Entry DOI | 10.2210/pdb9rpb/pdb |
| EMDB information | 54151 |
| Descriptor | Green fluorescent protein,Gamma-aminobutyric acid receptor subunit alpha-5, GAMMA-AMINO-BUTANOIC ACID, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (12 entities in total) |
| Functional Keywords | gabaa receptor, ion channel, pentameric ligand gated ion channel, a5 gaba receptor, membrane protein |
| Biological source | Aequorea victoria More |
| Total number of polymer chains | 6 |
| Total formula weight | 430989.59 |
| Authors | Cowgill, J.,Lindahl, E.,Howard, R.J. (deposition date: 2025-06-24, release date: 2026-03-18, Last modification date: 2026-07-08) |
| Primary citation | Cowgill, J.,Fan, C.,Steyaert, J.,Howard, R.J.,Lindahl, E. Structural basis for activation and potentiation in a human alpha 5 beta 3 GABA A receptor. Nat Commun, 17:-, 2026 Cited by PubMed Abstract: 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. PubMed: 42297817DOI: 10.1038/s41467-026-74279-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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