1pa9
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(New page: 200px<br /><applet load="1pa9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pa9, resolution 2.0Å" /> '''Yersinia Protein-Tyro...)
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Revision as of 21:30, 20 November 2007
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Yersinia Protein-Tyrosine Phosphatase complexed with pNCS (Yop51,Pasteurella X,Ptpase,Yop51delta162) (Catalytic Domain, Residues 163-468) Mutant With Cys 235 Replaced By Arg (C235r)
Overview
The pathogenic bacteria Yersinia are causative agents in human diseases, ranging from gastrointestinal syndromes to bubonic plague. There is, increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass, destruction. Because the phosphatase activity of the Yersinia protein, tyrosine phosphatase, YopH, is essential for virulence in the Yersinia, pathogen, potent and selective YopH inhibitors are expected to serve as, novel anti-plague agents. We have identified a specific YopH small, molecule inhibitor, p-nitrocatechol sulfate (pNCS), which exhibits a Ki, value of 25 microM for YopH and displays a 13-60-fold selectivity in favor, of YopH against a panel of mammalian PTPs. To facilitate the understanding, of the underlying molecular basis for tight binding and specificity, we, have determined the crystal structure of YopH in complex with pNCS at a, 2.0-A resolution. The structural data are corroborated by results from, kinetic analyses of the interactions of YopH and its site-directed mutants, with pNCS. The results show that while the interactions of the sulfuryl, moiety and the phenyl ring with the YopH active site contribute to pNCS, binding affinity, additional interactions of the hydroxyl and nitro groups, in pNCS with Asp-356, Gln-357, Arg-404, and Gln-446 are responsible for, the increased potency and selectivity. In particular, we note that, residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate, in a unique H-bonding network with the hydroxyl group ortho to the, sulfuryl moiety, which may be exploited to design more potent and specific, YopH inhibitors.
About this Structure
1PA9 is a Single protein structure of sequence from Yersinia enterocolitica with CSN as ligand. Active as Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Full crystallographic information is available from OCA.
Reference
Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor., Sun JP, Wu L, Fedorov AA, Almo SC, Zhang ZY, J Biol Chem. 2003 Aug 29;278(35):33392-9. Epub 2003 Jun 16. PMID:12810712
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