9CXB

Native human GABAA receptor of beta2-alpha1-beta1-alpha2-gamma2 assembly

9CXB の概要

• エントリーDOI: 10.2210/pdb9cxb/pdb
• EMDBエントリー: 45984
• 分子名称: Gamma-aminobutyric acid receptor subunit beta-2, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)-alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, GAMMA-AMINO-BUTANOIC ACID, ... (13 entities in total)
• 機能のキーワード: ion channels, heteropentamer, receptor, inhibitory., membrane protein
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 333660.94

構造登録者

Zhou, J.,Hibbs, R.E.,Noviello, C.M. (登録日: 2024-07-31, 公開日: 2025-01-22, 最終更新日: 2025-02-26)

主引用文献

Zhou, J.,Noviello, C.M.,Teng, J.,Moore, H.,Lega, B.,Hibbs, R.E.
Resolving native GABA A receptor structures from the human brain.
Nature, 638:562-568, 2025

PubMed Abstract: Type A GABA (γ-aminobutyric acid) receptors (GABA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA receptors in the human brain have been inferred from subunit localization in tissue, functional measurements and structural analysis from recombinant expression and in mice. However, the arrangements of subunits that co-assemble physiologically in native human GABA receptors remain unknown. Here we isolated α1 subunit-containing GABA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABA receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA receptor signalling and targeted pharmacology in the human brain.

PubMed: 39843743
DOI: 10.1038/s41586-024-08454-1

実験手法

ELECTRON MICROSCOPY (3.33 Å)