8OQ7
CryoEM structure of human rho1 GABAA receptor in complex with inhibitor TPMPA
Summary for 8OQ7
| Entry DOI | 10.2210/pdb8oq7/pdb |
| EMDB information | 17107 |
| Descriptor | Gamma-aminobutyric acid receptor subunit rho-1, methyl(1,2,3,6-tetrahydropyridin-4-yl)phosphinic acid, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total) |
| Functional Keywords | gabaa receptor, rho1, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 5 |
| Total formula weight | 287829.77 |
| Authors | Chen, F.,Victor, T.,John, C.,Rebecca, J.H.,Lindahl, E. (deposition date: 2023-04-11, release date: 2023-08-30, Last modification date: 2024-10-16) |
| Primary citation | Cowgill, J.,Fan, C.,Haloi, N.,Tobiasson, V.,Zhuang, Y.,Howard, R.J.,Lindahl, E. Structure and dynamics of differential ligand binding in the human rho-type GABA A receptor. Neuron, 111:3450-, 2023 Cited by PubMed Abstract: The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ρ-type GABARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels. PubMed: 37659407DOI: 10.1016/j.neuron.2023.08.006 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.2 Å) |
Structure validation
Download full validation report
