MM/PBSA studies on conformational changes of Yersinia Protein Tyrosine Phosphatase and use in structure-based inhibitor design

COMP 165

Xin Hu, hux@rockefeller.edu and C. Erec Stebbins, stebbins@rockefeller.edu. Laboratory of Structural Microbiology, The Rockefeller University, 1230 York Ave, New York, NY 10021
The bacterial protein tyrosine phosphatase (YopH) is an essential virulence determinant in Yersinia spp., which cause gastrointestinal diseases and the plague. These pathogens represent an important medical concern due to the emergence of antibiotic resistance and their potential use as biological weapons. Like eukaryotic PTPases, YopH catalyzes the hydrolysis of the phosphate moiety of phosphotyrosine within a highly conserved active binding pocket, which is characterized by the closure of the so-called "WPD loop" triggered by ligand binding. In the present work, we have studied the conformational changes and dynamic properties of the WPD loop by molecular dynamics simulations. The driving force of the conformational transition imposed by the phosphate or its analogues was investigated by free energy calculations using MM/PBSA, which allowed us to further evaluate the binding affinity of a diverse set of phosphate mimetics in good correlation with experimental results. Finally, we illustrate the use of MM/PBSA combined with docking and virtual screening in the development of novel, potent YopH inhibitors as antiplague drugs.
 

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Division of Computers in Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005