5L4H

X-ray structure of the 2-22' locally-closed mutant of GLIC in complex with 5-(2-BROMO-ETHYL)-5-ETHYL-PYRIMIDINE-2,4,6-TRIONE (brominated barbiturate)

5L4H の概要

• エントリーDOI: 10.2210/pdb5l4h/pdb
• 分子名称: Proton-gated ion channel, CHLORIDE ION, DODECYL-BETA-D-MALTOSIDE, ... (5 entities in total)
• 機能のキーワード: membrane protein, transport protein
• 由来する生物種: Gloeobacter violaceus (strain PCC 7421)
• 細胞内の位置: Cell inner membrane ; Multi- pass membrane protein : Q7NDN8
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 182078.99

構造登録者

Fourati, Z.,Ruza, R.R.,Delarue, M. (登録日: 2016-05-25, 公開日: 2016-12-21, 最終更新日: 2024-10-16)

主引用文献

Fourati, Z.,Ruza, R.R.,Laverty, D.,Drege, E.,Delarue-Cochin, S.,Joseph, D.,Koehl, P.,Smart, T.,Delarue, M.
Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State.
J. Biol. Chem., 292:1550-1558, 2017

PubMed Abstract: Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound to GLIC, a cationic prokaryotic pLGIC with excellent structural homology to other relevant channels sensitive to general anesthetics and, as shown here, to barbiturates, at clinically relevant concentrations. Several derivatives of barbiturates containing anomalous scatterers were synthesized, and these derivatives helped us unambiguously identify a unique barbiturate binding site within the central ion channel pore in a closed conformation. In addition, docking calculations around the observed binding site for all three states of the receptor, including a model of the desensitized state, showed that barbiturates preferentially stabilize the closed state. The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates.

PubMed: 27986812
DOI: 10.1074/jbc.M116.766964

実験手法

X-RAY DIFFRACTION (3.3 Å)