3v6m: Difference between revisions
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[[ | ==Inhibition of caspase-6 activity by single mutation outside the active site== | ||
<StructureSection load='3v6m' size='340' side='right' caption='[[3v6m]], [[Resolution|resolution]] 2.69Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3v6m]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V6M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V6M FirstGlance]. <br> | |||
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v6l|3v6l]], [[3nr2|3nr2]], [[3od5|3od5]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-6 Caspase-6], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.59 3.4.22.59] </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=3v6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v6m OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v6m RCSB], [http://www.ebi.ac.uk/pdbsum/3v6m PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug target due to its strong association with neurodegeneration and axonal pruning events as well as its crucial roles in Huntington disease and Alzheimer disease. CASP6 activity is suppressed by ARK5-mediated phosphorylation at Ser(257) with an unclear mechanism. In this work, we solved crystal structures of DeltaproCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6, respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics simulation studies revealed that phosphorylation on Ser(257) inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD(193)-bound "inhibited state." The structural and biochemical results also showed that phosphorylation on Ser(257) inhibited the CASP6 activity by steric hindrance. These results disclosed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design. | |||
Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays.,Cao Q, Wang XJ, Liu CW, Liu DF, Li LF, Gao YQ, Su XD J Biol Chem. 2012 May 4;287(19):15371-9. Epub 2012 Mar 20. PMID:22433863<ref>PMID:22433863</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Caspase|Caspase]] | *[[Caspase|Caspase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Caspase-6]] | [[Category: Caspase-6]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Cao, Q | [[Category: Cao, Q]] | ||
[[Category: Li, L F | [[Category: Li, L F]] | ||
[[Category: Liu, D F | [[Category: Liu, D F]] | ||
[[Category: Su, X D | [[Category: Su, X D]] | ||
[[Category: Wang, X J | [[Category: Wang, X J]] | ||
[[Category: Caspase domain]] | [[Category: Caspase domain]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
Revision as of 20:28, 9 December 2014
Inhibition of caspase-6 activity by single mutation outside the active siteInhibition of caspase-6 activity by single mutation outside the active site
Structural highlights
Publication Abstract from PubMedThe apoptotic effector caspase-6 (CASP6) has been clearly identified as a drug target due to its strong association with neurodegeneration and axonal pruning events as well as its crucial roles in Huntington disease and Alzheimer disease. CASP6 activity is suppressed by ARK5-mediated phosphorylation at Ser(257) with an unclear mechanism. In this work, we solved crystal structures of DeltaproCASP6S257E and p20/p10S257E, which mimicked the phosphorylated CASP6 zymogen and activated CASP6, respectively. The structural investigation combined with extensive biochemical assay and molecular dynamics simulation studies revealed that phosphorylation on Ser(257) inhibited self-activation of CASP6 zymogen by "locking" the enzyme in the TEVD(193)-bound "inhibited state." The structural and biochemical results also showed that phosphorylation on Ser(257) inhibited the CASP6 activity by steric hindrance. These results disclosed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design. Inhibitory mechanism of caspase-6 phosphorylation revealed by crystal structures, molecular dynamics simulations, and biochemical assays.,Cao Q, Wang XJ, Liu CW, Liu DF, Li LF, Gao YQ, Su XD J Biol Chem. 2012 May 4;287(19):15371-9. Epub 2012 Mar 20. PMID:22433863[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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