Journal
EMBO JOURNAL
Volume 28, Issue 19, Pages 3040-3051Publisher
WILEY
DOI: 10.1038/emboj.2009.227
Keywords
acetylcholine binding protein; anabaseine; crystal structure; nicotinic acetylcholine receptor; partial agonist
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Funding
- USPHS [R37-GM18360, UO1-DA019372, T32-GM07752]
- Pharmaceutical Research and Manufacturers Association Foundation
- NIH [MH-061412]
- European Commission [LSHG-CT-2006-031220]
- CNRS DREI-SDV
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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 alpha 7 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 angstrom 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 alpha 7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders. The EMBO Journal (2009) 28, 3040-3051. doi: 10.1038/emboj.2009.227; Published online 20 August 2009
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