1PA9

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)

Summary for 1PA9

• Entry DOI: 10.2210/pdb1pa9/pdb
• Descriptor: Protein-tyrosine phosphatase yopH, N,4-DIHYDROXY-N-OXO-3-(SULFOOXY)BENZENAMINIUM (3 entities in total)
• Functional Keywords: hydrolase, virulence
• Biological source: Yersinia enterocolitica
• Cellular location: Secreted: P15273
• Total number of polymer chains: 1
• Total formula weight: 31487.55

Authors

Sun, J.P.,Wu, L.,Fedorov, A.A.,Almo, S.C.,Zhang, Z.Y. (deposition date: 2003-05-13, release date: 2003-11-04, Last modification date: 2023-08-16)

Primary citation

Sun, J.P.,Wu, L.,Fedorov, A.A.,Almo, S.C.,Zhang, Z.Y.
Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor
J.BIOL.CHEM., 278:33392-33399, 2003

PubMed Abstract: 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.

PubMed: 12810712
DOI: 10.1074/jbc.M304693200

Experimental method

X-RAY DIFFRACTION (2 Å)