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== | ==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=''> | <StructureSection load='2y2f' size='340' side='right'caption='[[2y2f]], [[Resolution|resolution]] 1.78Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2y2f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pestis"_(lehmann_and_neumann_1896)_migula_1900 "bacillus pestis" (lehmann and neumann 1896) migula 1900]. 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:// | <table><tr><td colspan='2'>[[2y2f]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pestis"_(lehmann_and_neumann_1896)_migula_1900 "bacillus pestis" (lehmann and neumann 1896) migula 1900]. 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://proteopedia.org/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> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='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:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2y2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y2f OCA], [http://pdbe.org/2y2f PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2y2f RCSB], [http://www.ebi.ac.uk/pdbsum/2y2f PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2y2f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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==See Also== | ==See Also== | ||
*[[Tyrosine phosphatase|Tyrosine phosphatase]] | *[[Tyrosine phosphatase 3D structures|Tyrosine phosphatase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Bahta, M]] | [[Category: Bahta, M]] | ||
[[Category: Burke, T R]] | [[Category: Burke, T R]] | ||
Revision as of 15:31, 22 July 2020
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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