8OQA

CryoEM structure of human rho1 GABAA receptor in complex with GABA and picrotoxin

8OQA の概要

• エントリーDOI: 10.2210/pdb8oqa/pdb
• EMDBエントリー: 17110
• 分子名称: Gamma-aminobutyric acid receptor subunit rho-1, 2-acetamido-2-deoxy-beta-D-glucopyranose, HEXANE, ... (7 entities in total)
• 機能のキーワード: gabaa receptor, rho1, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 284505.39

構造登録者

Chen, F.,Victor, T.,John, C.,Rebecca, J.H.,Lindahl, E. (登録日: 2023-04-11, 公開日: 2023-08-30, 最終更新日: 2025-07-09)

主引用文献

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, 111:3450-3464.e5, 2023

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: 37659407
DOI: 10.1016/j.neuron.2023.08.006

実験手法

ELECTRON MICROSCOPY (2.9 Å)