PDBsum entry 2wn9

Receptor

PDB id: 2wn9

Contents

Protein chains

209 a.a.

Ligands

NAG-NAG-BMA-MAN-MAN

ZY5 ×5

NAG

Waters ×780

References listed in PDB file

Key reference

• Title: Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.
• Authors: R.E.Hibbs, G.Sulzenbacher, J.Shi, T.T.Talley, S.Conrod, W.R.Kem, P.Taylor, P.Marchot, Y.Bourne.
• Ref.: Embo J, 2009, 28, 3040-3051.
• PubMed id: 19696737

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.