title: Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin.
abstract: Oedema factor, a calmodulin-activated adenylyl cyclase, is important in the pathogenesis of anthrax. Here we report the X-ray structures of oedema factor with and without bound calmodulin. Oedema factor shares no significant structural homology with mammalian adenylyl cyclases or other proteins. In the active site, 3'-deoxy-ATP and a single metal ion are well positioned for catalysis with histidine 351 as the catalytic base. This mechanism differs from the mechanism of two-metal-ion catalysis proposed for mammalian adenylyl cyclases. Four discrete regions of oedema factor form a surface that recognizes an extended conformation of calmodulin, which is very different from the collapsed conformation observed in other structures of calmodulin bound to effector peptides. On calmodulin binding, an oedema factor helical domain of relative molecular mass 15,000 undergoes a 15 A translation and a 30 degrees rotation away from the oedema factor catalytic core, which stabilizes a disordered loop and leads to enzyme activation. These allosteric changes provide the first molecular details of how calmodulin modulates one of its targets.
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Chester L
authors.initials: CL
authors.lastname: Drum
authors.forename: Shui-Zhong
authors.initials: SZ
authors.lastname: Yan
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: Yue-Quan
authors.initials: YQ
authors.lastname: Shen
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.forename: Sandriyana
authors.initials: S
authors.lastname: Soelaiman
authors.forename: Zenon
authors.initials: Z
authors.lastname: Grabarek
authors.forename: Andrew
authors.initials: A
authors.lastname: Bohm
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000201:enzymology*; D001427:Bacterial Toxins; D002147:Calmodulin / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D005098:Exotoxins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002147:Calmodulin; D005098:Exotoxins; D046911:Macromolecular Substances; C030325:anthrax toxin; D000262:Adenylyl Cyclases