2WNL

CRYSTAL STRUCTURE OF APLYSIA ACHBP IN COMPLEX WITH ANABASEINE

Summary for 2WNL

• Entry DOI: 10.2210/pdb2wnl/pdb
• Related: 2BR7 2BR8 2BYN 2BYP 2BYQ 2BYR 2BYS 2C9T 2UZ6 2W8E 2W8F 2W8G 2WN9 2WNC 2WNJ
• Descriptor: SOLUBLE ACETYLCHOLINE RECEPTOR, 3,4,5,6-tetrahydro-2,3'-bipyridine, 5-amino-1-pyridin-3-ylpentan-1-one, ... (7 entities in total)
• Functional Keywords: receptor, anabaseine, acetylcholine binding protein
• Biological source: APLYSIA CALIFORNICA (CALIFORNIA SEA HARE)
• Total number of polymer chains: 10
• Total formula weight: 260972.21

Authors

Sulzenbacher, G.,Hibbs, R.,Shi, J.,Talley, T.,Conrod, S.,Kem, W.,Taylor, P.,Marchot, P.,Bourne, Y. (deposition date: 2009-07-09, release date: 2009-09-01, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)