Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal α7 nicotinic acetylcholine receptor

Ryan E. Hibbs, Gerlind Sulzenbacher, Jianxin Shi, Todd T. Talley, Sandrine Conrod, William R. Kem, Palmer Taylor, Pascale Marchot, Yves Bourne

Research output: Contribution to journalArticle

121 Scopus citations

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 α7 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 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 α7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)3040-3051
Number of pages12
JournalEMBO Journal
Volume28
Issue number19
DOIs
StatePublished - 2009

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Keywords

  • Acetylcholine binding protein
  • Anabaseine
  • Crystal structure
  • Nicotinic acetylcholine receptor
  • Partial agonist

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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