3deh: Difference between revisions
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==Crystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative Inhibitors== | ==Crystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative Inhibitors== | ||
<StructureSection load='3deh' size='340' side='right' caption='[[3deh]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='3deh' size='340' side='right' caption='[[3deh]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3deh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[3deh]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DEH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3DEH FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RXA:ISOQUINOLINE-1,3,4(2H)-TRIONE'>RXA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RXA:ISOQUINOLINE-1,3,4(2H)-TRIONE'>RXA</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=OCS:CYSTEINESULFONIC+ACID'>OCS</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=OCS:CYSTEINESULFONIC+ACID'>OCS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3dei|3dei]], [[3dej|3dej]], [[3dek|3dek]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3dei|3dei]], [[3dej|3dej]], [[3dek|3dek]]</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='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=3deh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3deh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3deh RCSB], [http://www.ebi.ac.uk/pdbsum/3deh 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=3deh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3deh OCA], [http://pdbe.org/3deh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3deh RCSB], [http://www.ebi.ac.uk/pdbsum/3deh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3deh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3deh ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3deh" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Caspase-3]] | [[Category: Caspase-3]] | ||
[[Category: | [[Category: Human]] | ||
[[Category: Ding, J]] | [[Category: Ding, J]] | ||
[[Category: Du, J]] | [[Category: Du, J]] | ||
Revision as of 16:55, 5 August 2016
Crystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative InhibitorsCrystal Structures of Caspase-3 with Bound Isoquinoline-1,3,4-trione Derivative Inhibitors
Structural highlights
Function[CASP3_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCaspase-3 is an attractive therapeutic target for treatment of diseases involving disregulated apoptosis. We report here the mechanism of caspase-3 inactivation by isoquinoline-1,3,4-trione derivatives. Kinetic analysis indicates the compounds can irreversibly inactivate caspase-3 in a 1,4-dithiothreitol (DTT)- and oxygen-dependent manner, implying that a redox cycle might take place in the inactivation process. Reactive oxygen species detection experiments using a chemical indicator, together with electron spin resonance measurement, suggest that ROS can be generated by reaction of isoquinoline-1,3,4-trione derivatives with DTT. Oxygen-free radical scavenger catalase and superoxide dismutase eliciting the inactivation of caspase-3 by the inhibitors confirm that ROS mediates the inactivation process. Crystal structures of caspase-3 in complexes with isoquinoline-1,3,4-trione derivatives show that the catalytic cysteine is oxidized to sulfonic acid (-SO(3)H) and isoquinoline-1,3,4-trione derivatives are bound at the dimer interface of caspase-3. Further mutagenesis study shows that the binding of the inhibitors with caspase-3 appears to be nonspecific. Isoquinoline-1,3,4-trione derivative-catalyzed caspase-3 inactivation could also be observed when DTT is substituted with dihydrolipoic acid, which exists widely in cells and might play an important role in the in vivo inactivation process in which the inhibitors inactivate caspase-3 in cells and then prevent the cells from apoptosis. These results provide valuable information for further development of small molecular inhibitors against caspase-3 or other oxidation-sensitive proteins. Isoquinoline-1,3,4-trione derivatives inactivate caspase-3 by generation of reactive oxygen species.,Du JQ, Wu J, Zhang HJ, Zhang YH, Qiu BY, Wu F, Chen YH, Li JY, Nan FJ, Ding JP, Li J J Biol Chem. 2008 Oct 31;283(44):30205-15. Epub 2008 Sep 2. PMID:18768468[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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