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A rapid oxime linker-based library approach to identification of bivalent inhibitors of the Yersinia pestis protein-tyrosine phosphatase, YopH.

ABSTRACT: A bivalent tethered approach toward YopH inhibitor development is presented that joins aldehydes with mixtures of bis-aminooxy-containing linkers using oxime coupling. The methodology is characterized by its facility and ease of use and its ability to rapidly identify low micromolar affinity inhibitors. The generality of the approach may potentially make it amenable to the development of bivalent inhibitors directed against other phosphatases.

SUBMITTER: Liu F

PROVIDER: S-EPMC2863121 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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A rapid oxime linker-based library approach to identification of bivalent inhibitors of the Yersinia pestis protein-tyrosine phosphatase, YopH.

Liu Fa F Hakami Ramin Mollaaghababa RM Dyas Beverly B Bahta Medhanit M Lountos George T GT Waugh David S DS Ulrich Robert G RG Burke Terrence R TR

Bioorganic & medicinal chemistry letters 20100315 9

A bivalent tethered approach toward YopH inhibitor development is presented that joins aldehydes with mixtures of bis-aminooxy-containing linkers using oxime coupling. The methodology is characterized by its facility and ease of use and its ability to rapidly identify low micromolar affinity inhibitors. The generality of the approach may potentially make it amenable to the development of bivalent inhibitors directed against other phosphatases. ...[more]

PMID: 20350805

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Yersinia pestis genotyping.

Project description: Not available

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Dynamics of the WPD loop of the Yersinia protein tyrosine phosphatase.

Project description:The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia spp., causing gastrointestinal diseases and the plague. Like eukaryotic PTPases, YopH catalyzes the hydrolysis of the phosphate moiety of phosphotyrosine within a highly conserved binding pocket, which is also characterized by the closure of the so-called "WPD loop" upon ligand binding. In this study, we investigate the conformational changes and dynamics of the WPD loop by molecular dynamics simulations. Consistent with experimental observations, our simulations show that the WPD loop of YopH is intrinsically flexible and fluctuates between the open and closed conformation with a frequency of approximately 4 ns for the apo, native protein. The region of helix alpha4 spanning loop 384-392, which has been revealed experimentally as a second substrate-binding site in YopH, is found to be highly associated with the WPD loop, stabilizing it in the closed, active conformation, and providing a structural basis for the cooperation of the second-substrate binding site in substrate recognition. Loop L4 (residues 323-327) is shown to be involved in a parallel, correlated motion mode with the WPD loop that contributes the stabilization of a more extended open conformation. In addition, we have simulated the loop reopening in the ligand-bound protein complex by applying the locally enhanced sampling method. Finally, the dynamic behavior of the WPD loop for the C403S mutant differs from the wild-type YopH remarkably. These results shed light on the role of the WPD loop in PTPase-mediated catalysis, and are useful in structure-based design for novel, selective YopH inhibitors as antibacterial drugs.

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