4qub: Difference between revisions
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''' | ==Caspase-3 K137A== | ||
<StructureSection load='4qub' size='340' side='right' caption='[[4qub]], [[Resolution|resolution]] 1.69Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4qub]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QUB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QUB FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZI:AZIDE+ION'>AZI</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qtx|4qtx]], [[4qty|4qty]], [[4qu0|4qu0]], [[4qu5|4qu5]], [[4qu8|4qu8]], [[4qu9|4qu9]], [[4qua|4qua]], [[4qud|4qud]], [[4que|4que]], [[4qug|4qug]], [[4quh|4quh]], [[4qui|4qui]], [[4quj|4quj]], [[4qul|4qul]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-3 Caspase-3], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.56 3.4.22.56] </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=4qub FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qub OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qub RCSB], [http://www.ebi.ac.uk/pdbsum/4qub PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Caspases have several allosteric sites that bind small molecules or peptides. Allosteric regulators are known to affect caspase enzyme activity, in general, by facilitating large conformational changes that convert the active enzyme to a zymogen-like form in which the substrate-binding pocket is disordered. Mutations in presumed allosteric networks also decrease activity, although large structural changes are not observed. Mutation of the central V266 to histidine in the dimer interface of caspase-3 inactivates the enzyme by introducing steric clashes that may ultimately affect positioning of a helix on the protein surface. The helix is thought to connect several residues in the active site to the allosteric dimer interface. In contrast to the effects of small molecule allosteric regulators, the substrate-binding pocket is intact in the mutant, yet the enzyme is inactive. We have examined the putative allosteric network, in particular the role of helix 3, by mutating several residues in the network. We reduced steric clashes in the context of caspase-3(V266H), and we show that activity is restored, particularly when the restorative mutation is close to H266. We also mimicked the V266H mutant by introducing steric clashes elsewhere in the allosteric network, generating several mutants with reduced activity. Overall, the data show that the caspase-3 native ensemble includes the canonical active state as well as an inactive conformation characterized by an intact substrate-binding pocket, but with an altered helix 3. The enzyme activity reflects the relative population of each species in the native ensemble. | |||
Modifying Caspase-3 Activity by Altering Allosteric Networks.,Cade C, Swartz P, MacKenzie SH, Clark AC Biochemistry. 2014 Oct 24. PMID:25343534<ref>PMID:25343534</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Caspase-3]] | |||
[[Category: Cade, C.]] | |||
[[Category: Clark, A C.]] | |||
[[Category: MacKenzie, S H.]] | |||
[[Category: Swartz, P D.]] | |||
[[Category: Allosteric network]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
Revision as of 11:51, 5 November 2014
Caspase-3 K137ACaspase-3 K137A
Structural highlights
Publication Abstract from PubMedCaspases have several allosteric sites that bind small molecules or peptides. Allosteric regulators are known to affect caspase enzyme activity, in general, by facilitating large conformational changes that convert the active enzyme to a zymogen-like form in which the substrate-binding pocket is disordered. Mutations in presumed allosteric networks also decrease activity, although large structural changes are not observed. Mutation of the central V266 to histidine in the dimer interface of caspase-3 inactivates the enzyme by introducing steric clashes that may ultimately affect positioning of a helix on the protein surface. The helix is thought to connect several residues in the active site to the allosteric dimer interface. In contrast to the effects of small molecule allosteric regulators, the substrate-binding pocket is intact in the mutant, yet the enzyme is inactive. We have examined the putative allosteric network, in particular the role of helix 3, by mutating several residues in the network. We reduced steric clashes in the context of caspase-3(V266H), and we show that activity is restored, particularly when the restorative mutation is close to H266. We also mimicked the V266H mutant by introducing steric clashes elsewhere in the allosteric network, generating several mutants with reduced activity. Overall, the data show that the caspase-3 native ensemble includes the canonical active state as well as an inactive conformation characterized by an intact substrate-binding pocket, but with an altered helix 3. The enzyme activity reflects the relative population of each species in the native ensemble. Modifying Caspase-3 Activity by Altering Allosteric Networks.,Cade C, Swartz P, MacKenzie SH, Clark AC Biochemistry. 2014 Oct 24. PMID:25343534[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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