2y2f: Difference between revisions
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[[ | ==CRYSTAL STRUCTURE OF YERSINIA PESTIS YOPH IN COMPLEX WITH AN AMINOOXY-CONTAINING PLATFORM COMPOUND FOR INHIBITOR DESIGN== | ||
<StructureSection load='2y2f' size='340' side='right' caption='[[2y2f]], [[Resolution|resolution]] 1.78Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2y2f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Yersinia_pestis Yersinia pestis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y2F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y2F FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=YI1:[4-[3-(DIFLUORO-PHOSPHONO-METHYL)PHENYL]PHENYL]METHOXYAZANIUM'>YI1</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qz0|1qz0]]</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2y2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y2f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y2f RCSB], [http://www.ebi.ac.uk/pdbsum/2y2f PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Our 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<ref>PMID:21443195</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Tyrosine phosphatase|Tyrosine phosphatase]] | *[[Tyrosine phosphatase|Tyrosine phosphatase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Yersinia pestis]] | [[Category: Yersinia pestis]] | ||
[[Category: Bahta, M.]] | [[Category: Bahta, M.]] | ||
