4zvz: Difference between revisions

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OCA

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 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4zx2|4zx2]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </span></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=4zvz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zvz OCA], [http://pdbe.org/4zvz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zvz RCSB], [http://www.ebi.ac.uk/pdbsum/4zvz PDBsum]</span></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=4zvz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zvz OCA], [http://pdbe.org/4zvz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4zvz RCSB], [http://www.ebi.ac.uk/pdbsum/4zvz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4zvz ProSAT]</span></td></tr>
 </table>
 == Function ==
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 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Serine/threonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 A. From this structure we propose a mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a conserved Asp271-M1:M2-W1-His427-His304-Asp274 catalytic motif (where M1 and M2 are metals and W1 is a water molecule). The structure of PP5c provides a structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.
+Cantharidin is a natural toxin and an active constituent in a traditional Chinese medicine used to treat tumors. Cantharidin acts as a semi-selective inhibitor of PPP-family ser/thr protein phosphatases. Despite sharing a common catalytic mechanism and marked structural similarity with PP1C, PP2AC and PP5C, human PP4C was found to be insensitive to the inhibitory activity of cantharidin. To explore the molecular basis for this selectivity, we synthesized and tested novel C5/C6-derivatives designed from quantum-based modeling of the interactions revealed in the co-crystal structures of PP5C in complex with cantharidin. Structure-activity relationship studies and analysis of high-resolution (1.25A) PP5C-inhibitor co-crystal structures reveal close contacts between the inhibitor bridgehead oxygen and both a catalytic metal ion and a non-catalytic phenylalanine residue, the latter of which is substituted by tryptophan in PP4C. Quantum chemistry calculations predicted that steric clashes with the bulkier tryptophan side chain in PP4C would force all cantharidin-based inhibitors into an unfavorable binding mode, disrupting the strong coordination of active site metal ions observed in the PP5C co-crystal structures, thereby rendering PP4C insensitive to the inhibitors. This prediction was confirmed by inhibition studies employing native human PP4C. Mutation of PP5C (F446W) and PP1C (F257W), to mimic the PP4C active site, resulted in markedly suppressed sensitivity to cantharidin. These observations provide insight into the structural basis for the natural selectivity of cantharidin and provide an avenue for PP4C deselection. The novel crystal structures also provide insight into interactions that provide increased selectivity of the C5/C6 modifications for PP5C versus other PPP-family phosphatases.
-Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5.,Swingle MR, Honkanen RE, Ciszak EM J Biol Chem. 2004 Aug 6;279(32):33992-9. Epub 2004 May 23. PMID:15155720<ref>PMID:15155720</ref>
+Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C.,Chattopadhyay D, Swingle MR, Salter EA, Wood E, D'Arcy B, Zivanov C, Abney K, Musiyenko A, Rusin SF, Kettenbach A, Yet L, Schroeder CE, Golden JE, Dunham WH, Gingras AC, Banerjee S, Forbes D, Wierzbicki A, Honkanen RE Biochem Pharmacol. 2016 Jun 1;109:14-26. doi: 10.1016/j.bcp.2016.03.011. Epub, 2016 Mar 23. PMID:27002182<ref>PMID:27002182</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
 <div class="pdbe-citations 4zvz" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Serine/threonine protein phosphatase|Serine/threonine protein phosphatase]]
 == References ==
 <references/>