2WNC

Crystal structure of Aplysia ACHBP in complex with tropisetron

2WNC の概要

• エントリーDOI: 10.2210/pdb2wnc/pdb
• 関連するPDBエントリー: 2BR7 2BR8 2BYN 2BYP 2BYQ 2BYR 2BYS 2C9T 2UZ6 2W8E 2W8F 2W8G 2WN9
• 分子名称: Soluble acetylcholine receptor, (3-ENDO)-8-METHYL-8-AZABICYCLO[3.2.1]OCT-3-YL 1H-INDOLE-3-CARBOXYLATE (3 entities in total)
• 機能のキーワード: choline-binding protein, receptor, acetylcholine binding protein
• 由来する生物種: Aplysia californica (California sea hare)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 130685.49

構造登録者

Sulzenbacher, G.,Hibbs, R.,Shi, J.,Talley, T.,Conrod, S.,Kem, W.,Taylor, P.,Marchot, P.,Bourne, Y. (登録日: 2009-07-08, 公開日: 2009-09-01, 最終更新日: 2024-11-13)

主引用文献

Hibbs, R.E.,Sulzenbacher, G.,Shi, J.,Talley, T.T.,Conrod, S.,Kem, W.R.,Taylor, P.,Marchot, P.,Bourne, Y.
Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
EMBO J., 28:3040-3051, 2009

PubMed Abstract: The pentameric acetylcholine-binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the alpha7 receptor, 3-(2,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, were solved at 2.7-1.75 A resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing alpha7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.

PubMed: 19696737
DOI: 10.1038/emboj.2009.227

実験手法

X-RAY DIFFRACTION (2.2 Å)