| Abstract
| - Yersinia pestis, the causative agent of bubonic plague, secretes a eukaryotic-like protein tyrosinephosphatase (PTPase) termed Yersinia outer protein H (YopH) that is essential for virulence. We havedetermined, for the first time, the crystal structure of the YopH PTPase domain in complex with anonhydrolyzable substrate analogue, the hexapeptide mimetic Ac-DADE-F2Pmp-L-NH2. As anticipated,the mode of ligand binding in the active site is similar to the way in which the correspondingphosphohexapeptide binds to the structurally homologous human PTP1B. Unexpectedly, however, thecrystal structure also revealed a second substrate-binding site in YopH that is not present in PTP1B. Themode of binding and structural conformation of the hexapeptide analogue is quite different in the twosites. Although the biological function of the second substrate-binding site remains to be investigated, thestructure of a substrate analogue in the active site of Y. pestis YopH opens the door for the structure-based design and optimization of therapeutic countermeasures to combat this potential agent of bioterrorism.
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