Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin

@article{Drum2002StructuralBF,
  title={Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin},
  author={Chester Lee Drum and Shui-Zhong Yan and Joel Bard and Yue-quan Shen and Dan Lu and Sandriyana Soelaiman and Zenon Grabarek and Andrew Bohm and Wei-Jen Tang},
  journal={Nature},
  year={2002},
  volume={415},
  pages={396-402}
}
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… 
Structural and Kinetic Analyses of the Interaction of Anthrax Adenylyl Cyclase Toxin with Reaction Products cAMP and Pyrophosphate*[boxs]
TLDR
The structure of EF·CaM in complex with its reaction products, cAMP and PPi is reported, and it is hypothesized that EF could use a “histidine and two-metal ion” hybrid mechanism to facilitate the cyclization reaction.
The adenylyl cyclase activity of anthrax edema factor.
Anthrax Edema Factor: An Ion-Adaptive Mechanism of Catalysis with Increased Transition-State Conformational Flexibility.
TLDR
It is found that EF catalysis is possible, and faster than that of mACs, in both one and two Mg(2+)-ion-binding modes, providing adaptive plasticity to host-cell environments and representing an entropic advantage for catalytic efficiency.
ATP conformations and ion binding modes in the active site of anthrax edema factor: A computational analysis
TLDR
It is proposed that the conformation observed in the one‐ion crystal structure is a more probable starting point for the reaction, and the simulations suggest that a C3′‐endo sugar pucker facilitates nucleophilic attack.
Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins
TLDR
Using spectroscopic, enzyme kinetic and surface plasmon resonance spectroscopy analyses, it is shown that low Ca2+ concentrations increase the affinity of CaM for EF and CyaA causing their activation, but higher Ca2- concentrations directly inhibit catalysis.
Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin
CyaA is crucial for colonization by Bordetella pertussis, the etiologic agent of whooping cough. Here we report crystal structures of the adenylyl cyclase domain (ACD) of CyaA with the C‐terminal
Molecular Motions as a Drug Target: Mechanistic Simulations of Anthrax Toxin Edema Factor Function Led to the Discovery of Novel Allosteric Inhibitors
TLDR
Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars.
Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor
TLDR
Excess cAMP production and the associated impairment of host defence may be afforded even under oxidative conditions in activated neutrophils.
Calcium Dependence of the Interaction between Calmodulin and Anthrax Edema Factor*
TLDR
This work has shown that backbone chemical shift perturbations of CaM show that EF interacts weakly with the N-terminal domain of apoCaM, which differs from that observed for most other CaM targets, which normally interact only with the Ca2+-bound CaM domains and become active following the transition to the fourCa2+ state.
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TLDR
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TLDR
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TLDR
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TLDR
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