Linked Life Data

12810712

Source:http://linkedlifedata.com/resource/pubmed/id/12810712

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
35
pubmed:dateCreated
2003-8-25
pubmed:databankReference
pubmed:abstractText
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:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
278
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
33392-9
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12810712-Amino Acid Sequence, pubmed-meshheading:12810712-Arginine, pubmed-meshheading:12810712-Asparagine, pubmed-meshheading:12810712-Bacterial Outer Membrane Proteins, pubmed-meshheading:12810712-Catalytic Domain, pubmed-meshheading:12810712-Catechols, pubmed-meshheading:12810712-Crystallography, X-Ray, pubmed-meshheading:12810712-DNA Mutational Analysis, pubmed-meshheading:12810712-Dose-Response Relationship, Drug, pubmed-meshheading:12810712-Glutamic Acid, pubmed-meshheading:12810712-Hydrolysis, pubmed-meshheading:12810712-Kinetics, pubmed-meshheading:12810712-Models, Chemical, pubmed-meshheading:12810712-Models, Molecular, pubmed-meshheading:12810712-Molecular Sequence Data, pubmed-meshheading:12810712-Mutagenesis, Site-Directed, pubmed-meshheading:12810712-Protein Binding, pubmed-meshheading:12810712-Protein Conformation, pubmed-meshheading:12810712-Protein Structure, Tertiary, pubmed-meshheading:12810712-Protein Tyrosine Phosphatases, pubmed-meshheading:12810712-Sequence Homology, Amino Acid, pubmed-meshheading:12810712-Yersinia pestis
pubmed:year
2003
pubmed:articleTitle
Crystal structure of the Yersinia protein-tyrosine phosphatase YopH complexed with a specific small molecule inhibitor.
pubmed:affiliation
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't