title: Experimentally based model of a complex between a snake toxin and the alpha 7 nicotinic receptor.
abstract: To understand how snake neurotoxins interact with nicotinic acetylcholine receptors, we have elaborated an experimentally based model of the alpha-cobratoxin-alpha7 receptor complex. This model was achieved by using (i) a three-dimensional model of the alpha7 extracellular domain derived from the crystallographic structure of the homologous acetylcholine-binding protein, (ii) the previously solved x-ray structure of the toxin, and (iii) nine pairs of residues identified by cycle-mutant experiments to make contacts between the alpha-cobratoxin and alpha7 receptor. Because the receptor loop F occludes entrance of the toxin binding pocket, we submitted this loop to a dynamics simulation and selected a conformation that allowed the toxin to reach its binding site. The three-dimensional structure of the toxin-receptor complex model was validated a posteriori by an additional double-mutant experiment. The model shows that the toxin interacts perpendicularly to the receptor axis, in an equatorial position of the extracellular domain. The tip of the toxin central loop plugs into the receptor between two subunits, just below the functional receptor loop C, the C-terminal tail of the toxin making adjacent additional interactions at the receptor surface. The receptor establishes major contacts with the toxin by its loop C, which is assisted by principal (loops A and B) and complementary (loops D, F, and 1) functional regions. This model explains the antagonistic properties of the toxin toward the neuronal receptor and opens the way to the design of new antagonists.
authors.affiliation: Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines, 91191 Gif-sur-Yvette Cedex, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Fruchart-Gaillard
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilquin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Antil-Delbeke
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le Novère
authors.forename: Toru
authors.initials: T
authors.lastname: Tamiya
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Corringer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.forename: André
authors.initials: A
authors.lastname: Ménez
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003039:Cobra Neurotoxin Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D017815:Elapidae; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D003039:Cobra Neurotoxin Proteins; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C025154:alpha-cobratoxin