6CDU

Crystal structure of a chimeric human alpha1GABAA receptor in complex with alphaxalone

6CDU の概要

• エントリーDOI: 10.2210/pdb6cdu/pdb
• 分子名称: chimeric alpha1GABAA receptor, (3a,5a)-3-Hydroxypregnane-11,20-dione (2 entities in total)
• 機能のキーワード: gabaa receptor, anesthetics, alphaxalone, neurosteroids, protein transport
• 由来する生物種: Dickeya dadantii (strain 3937) (Erwinia chrysanthemi (strain 3937)); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 375578.36

構造登録者

Chen, Q.,Arjunan, P.,Cohen, A.E.,Xu, Y.,Tang, P. (登録日: 2018-02-09, 公開日: 2018-08-22, 最終更新日: 2023-10-04)

主引用文献

Chen, Q.,Wells, M.M.,Arjunan, P.,Tillman, T.S.,Cohen, A.E.,Xu, Y.,Tang, P.
Structural basis of neurosteroid anesthetic action on GABAAreceptors.
Nat Commun, 9:3972-3972, 2018

PubMed Abstract: Type A γ-aminobutyric acid receptors (GABARs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABAR transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABAR structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABAR (ELIC-α1GABAR). The chimera retains the functional and pharmacological properties of GABARs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1-TM2 linker. The study provides a framework to discover new GABAR modulators with therapeutic potential.

PubMed: 30266951
DOI: 10.1038/s41467-018-06361-4

実験手法

X-RAY DIFFRACTION (3.45 Å)