Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor

Jin Peng Sun, Li Wu, Alexander A. Fedorov, Steven C. Almo, Zhong Yin Zhang

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 μM 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-Å 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.

Original languageEnglish (US)
Pages (from-to)33392-33399
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number35
DOIs
StatePublished - Aug 29 2003

Fingerprint

Yersinia
Protein Tyrosine Phosphatases
Crystal structure
Molecules
Plague
Hydroxyl Radical
Yersinia pestis
Weapons
Gastrointestinal Diseases
Military operations
Pathogens
Phosphoric Monoester Hydrolases
Virulence
Catalytic Domain
Bacteria
4-nitrocatechol sulfate
Kinetics
Water

ASJC Scopus subject areas

  • Biochemistry

Cite this

Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor. / Sun, Jin Peng; Wu, Li; Fedorov, Alexander A.; Almo, Steven C.; Zhang, Zhong Yin.

In: Journal of Biological Chemistry, Vol. 278, No. 35, 29.08.2003, p. 33392-33399.

Research output: Contribution to journalArticle

Sun, Jin Peng ; Wu, Li ; Fedorov, Alexander A. ; Almo, Steven C. ; Zhang, Zhong Yin. / Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 35. pp. 33392-33399.
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