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  • The EMBO Journal (2005) 24, 3635 - 3646
  • doi:10.1038/sj.emboj.7600828

Published online: 29 September 2005

Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations

Scott B Hansen1,2, Gerlind Sulzenbacher3, Tom Huxford2, Pascale Marchot4, Palmer Taylor1 and Yves Bourne3

  1. Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA
  2. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, USA
  3. Architecture et Fonction des Macromolécules Biologiques, CNRS UMR-6098, Marseille, France
  4. Ingénierie des Protéines, CNRS FRE-2738, Institut Fédératif de Recherche Jean Roche, Université de la Méditerranée, Faculté de Médecine Secteur Nord, Marseille, France

Correspondence to:

Palmer Taylor, Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0636, USA. Tel.: +1 858 534 1366; Fax: +1 858 534 8248; E-mail: pwtaylor@ucsd.edu

Yves Bourne, Architecture et Fonction des Macromolécules Biologiques, CNRS UMR-6098, Campus Luminy—Case 932, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France. Tel.: +33 4 91 82 55 66; Fax: +33 4 91 26 27 20; E-mail: yves.bourne@afmb.univ-mrs.fr

Received 23 June 2005; Accepted 7 September 2005

Upon ligand binding at the subunit interfaces, the extracellular domain of the nicotinic acetylcholine receptor undergoes conformational changes, and agonist binding allosterically triggers opening of the ion channel. The soluble acetylcholine-binding protein (AChBP) from snail has been shown to be a structural and functional surrogate of the ligand-binding domain (LBD) of the receptor. Yet, individual AChBP species display disparate affinities for nicotinic ligands. The crystal structure of AChBP from Aplysia californica in the apo form reveals a more open loop C and distinctive positions for other surface loops, compared with previous structures. Analysis of Aplysia AChBP complexes with nicotinic ligands shows that loop C, which does not significantly change conformation upon binding of the antagonist, methyllycaconitine, further opens to accommodate the peptidic antagonist, alpha-conotoxin ImI, but wraps around the agonists lobeline and epibatidine. The structures also reveal extended and nonoverlapping interaction surfaces for the two antagonists, outside the binding loci for agonists. This comprehensive set of structures reflects a dynamic template for delineating further conformational changes of the LBD of the nicotinic receptor.

  • Keywords:

    • acetylcholine-binding protein,
    • alpha-conotoxin,
    • conformational flexibility,
    • crystal structure,
    • nicotinic acetylcholine receptor