8SGO

Human GABAA receptor alpha1-beta2-gamma2 subtype in complex with GABA plus pregnenolone sulfate

8SGO の概要

• エントリーDOI: 10.2210/pdb8sgo/pdb
• EMDBエントリー: 40462
• 分子名称: Gamma-aminobutyric acid receptor subunit beta-2, GAMMA-AMINO-BUTANOIC ACID, PHOSPHATIDYLETHANOLAMINE, ... (13 entities in total)
• 機能のキーワード: ion channel, neurosteroids, transport protein-immune system complex, transport protein/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 9
• 化学式量合計: 370168.68

構造登録者

Legesse, D.H.,Fan, C.,Teng, J.,Zhuang, Y.,Howard, R.J.,Noviello, C.M.,Lindahl, E.,Hibbs, R.E. (登録日: 2023-04-12, 公開日: 2023-08-30, 最終更新日: 2024-11-20)

主引用文献

Legesse, D.H.,Fan, C.,Teng, J.,Zhuang, Y.,Howard, R.J.,Noviello, C.M.,Lindahl, E.,Hibbs, R.E.
Structural insights into opposing actions of neurosteroids on GABA A receptors.
Nat Commun, 14:5091-5091, 2023

PubMed Abstract: γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.

PubMed: 37607940
DOI: 10.1038/s41467-023-40800-1

実験手法

ELECTRON MICROSCOPY (2.65 Å)