Interfering with the Host-Pathogen Interaction of Bordetella Pertussis

The adenyl cyclases EF and CyaA play an important role into the virulence of the agent of whopping cough (B.pertussis) and of the agent of anthrax (B.anthracis). Indeed, their interaction with calmodulin (CaM), leads to cAMP overproduction, disorganizing the signaling network into the host cell. The numerous structures of EF recently allowed some of us to analyze dynamics and energetics of EF-CaM (1-2, 4, 6) and to discover a new family of EF inhibitors (5).The analysis of the interaction between CaM and the catalytic domain (AC) of CyaA was more difficult to handle, as only the X-ray crystallographic structure of the complex of AC with the C terminal lobe of calmodulin (C-CaM) was know. Qualitative information was available on the conformations of isolated AC, revealing a less elongated shape than in the complex with C-CaM.Molecular dynamics simulations (7) predict three residues, R338, N347 and D360, to stabilize the AC/CaM interaction. Furthermore, their experimental mutations show significant decrease of the AC affinity for CaM, involving these residues in long-range allosteric communication between CaM and the AC catalytic site. Advanced molecular dynamics simulations, based on the TAMD approach(3), were used to investigate conformational landscape of the isolated AC and to propose compacted AC structures.1. Laine, Yoneda, Blondel, Malliavin Proteins 71,1813 (2008)2. Laine, Blondel, Malliavin Biophysical J. 96, 1249 (2009)3. Maragliano, Vanden-Eijnden Chem Phys Lett 426, 168 (2006)4. Martinez, Laine, Malliavin, Nilges, Blondel Proteins 77, 971 (2009)5. Laine, Goncalves, Karst, Lesnard, Rault, Tang, Malliavin, Ladant, Blondel Proc Natl Acad Sci U S A. 107, 11277 (2010)6. Laine, Martinez, Blondel, Malliavin Biophys J. 99, 2264 (2010)7. Selwa, Laine, Malliavin Proteins 80, 1028 (2012)