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  • The EMBO Journal (2009) 28, 3040 - 3051
  • doi:10.1038/emboj.2009.227

Published online: 20 August 2009

Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor

Ryan E Hibbs1,56, Gerlind Sulzenbacher2,6, Jianxin Shi1,7, Todd T Talley1, Sandrine Conrod3, William R Kem4, Palmer Taylor1, Pascale Marchot3 and Yves Bourne2

  1. Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
  2. Architecture et Fonction des Macromolécules Biologiques (AFMB, UMR-6098) CNRS, Université d'Aix-Marseille, Campus Luminy, Marseille, France
  3. ToxCiM, Département de Signalisation Neuronale, Centre de Recherche en Neurobiologie-Neurophysiologie de Marseille (CRN2M, CNRS UMR-6231), Université d'Aix-Marseille, Faculté de Médecine Secteur Nord, Marseille, France
  4. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA

Correspondence to:

Yves Bourne, Architecture et Fonction des Macromolécules Biologiques, UMR-6098, Case 932 - Campus de Luminy-163 Avenue de Luminy, F-13288 Marseille Cedex 09. Tel.: +33 4 91 82 55 66; Fax: +33 4 91 26 67 20; E-mail: yves.bourne@afmb.univ-mrs.fr

Palmer Taylor, Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0657, USA. Tel.: +1 858 534 1366; Fax: +1 858 534 8248; E-mail: pwtaylor@ucsd.edu

5Present address: Vollum Institute, Oregon Health and Science University, Portland, OR, USA

7Present address: Genomics Institute of the Novartis Research Foundation, La Jolla, CA, USA

6These authors contributed equally to this work

Received 7 April 2009; Accepted 14 July 2009

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 Å 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.

  • Keywords:

    • acetylcholine binding protein,
    • anabaseine,
    • crystal structure,
    • nicotinic acetylcholine receptor,
    • partial agonist