2y2f: Difference between revisions
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[[Category: Yersinia pestis]] | [[Category: Yersinia pestis]] | ||
[[Category: Bahta, M | [[Category: Bahta, M]] | ||
[[Category: Burke, T R | [[Category: Burke, T R]] | ||
[[Category: Dyas, B | [[Category: Dyas, B]] | ||
[[Category: Lountos, G T | [[Category: Lountos, G T]] | ||
[[Category: Ulrich, R G | [[Category: Ulrich, R G]] | ||
[[Category: Waugh, D S | [[Category: Waugh, D S]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Protein tyrosine phosphatase]] | [[Category: Protein tyrosine phosphatase]] | ||
Revision as of 10:50, 25 January 2015
CRYSTAL STRUCTURE OF YERSINIA PESTIS YOPH IN COMPLEX WITH AN AMINOOXY-CONTAINING PLATFORM COMPOUND FOR INHIBITOR DESIGNCRYSTAL STRUCTURE OF YERSINIA PESTIS YOPH IN COMPLEX WITH AN AMINOOXY-CONTAINING PLATFORM COMPOUND FOR INHIBITOR DESIGN
Structural highlights
Publication Abstract from PubMedOur current study reports the first K(M) optimization of a library of nitrophenylphosphate-containing substrates for generating an inhibitor lead against the Yersinia pestis outer protein phosphatase (YopH). A high activity substrate identified by this method (K(M) = 80 muM) was converted from a substrate into an inhibitor by replacement of its phosphate group with difluoromethylphosphonic acid and by attachment of an aminooxy handle for further structural optimization by oxime ligation. A cocrystal structure of this aminooxy-containing platform in complex with YopH allowed the identification of a conserved water molecule proximal to the aminooxy group that was subsequently employed for the design of furanyl-based oxime derivatives. By this process, a potent (IC(50) = 190 nM) and nonpromiscuous inhibitor was developed with good YopH selectivity relative to a panel of phosphatases. The inhibitor showed significant inhibition of intracellular Y. pestis replication at a noncytotoxic concentration. The current work presents general approaches to PTP inhibitor development that may be useful beyond YopH. Utilization of nitrophenylphosphates and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis outer protein H (YopH) phosphatase.,Bahta M, Lountos GT, Dyas B, Kim SE, Ulrich RG, Waugh DS, Burke TR Jr J Med Chem. 2011 Apr 28;54(8):2933-43. Epub 2011 Mar 28. PMID:21443195[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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