2c2m: Difference between revisions
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<StructureSection load='2c2m' size='340' side='right'caption='[[2c2m]], [[Resolution|resolution]] 1.94Å' scene=''> | <StructureSection load='2c2m' size='340' side='right'caption='[[2c2m]], [[Resolution|resolution]] 1.94Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2c2m]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C2M OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[2c2m]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C2M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C2M FirstGlance]. <br> | ||
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MX4:{1-[4-(BENZYLOXY)-4-OXOBUTANOYL]HYDRAZINO}ACETIC+ACID'>MX4</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MX4:{1-[4-(BENZYLOXY)-4-OXOBUTANOYL]HYDRAZINO}ACETIC+ACID'>MX4</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cp3|1cp3]], [[1gfw|1gfw]], [[1i3o|1i3o]], [[1nme|1nme]], [[1nmq|1nmq]], [[1nms|1nms]], [[1pau|1pau]], [[1qx3|1qx3]], [[1re1|1re1]], [[1rhj|1rhj]], [[1rhk|1rhk]], [[1rhm|1rhm]], [[1rhq|1rhq]], [[1rhr|1rhr]], [[1rhu|1rhu]], [[2c1e|2c1e]], [[2c2k|2c2k]], [[2c2o|2c2o]], [[2cdr|2cdr]], [[2cjx|2cjx]], [[2cjy|2cjy]], [[2cnk|2cnk]], [[2cnl|2cnl]], [[2cnn|2cnn]], [[2cno|2cno]], [[2j30|2j30]], [[2j31|2j31]], [[2j32|2j32]], [[2j33|2j33]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1cp3|1cp3]], [[1gfw|1gfw]], [[1i3o|1i3o]], [[1nme|1nme]], [[1nmq|1nmq]], [[1nms|1nms]], [[1pau|1pau]], [[1qx3|1qx3]], [[1re1|1re1]], [[1rhj|1rhj]], [[1rhk|1rhk]], [[1rhm|1rhm]], [[1rhq|1rhq]], [[1rhr|1rhr]], [[1rhu|1rhu]], [[2c1e|2c1e]], [[2c2k|2c2k]], [[2c2o|2c2o]], [[2cdr|2cdr]], [[2cjx|2cjx]], [[2cjy|2cjy]], [[2cnk|2cnk]], [[2cnl|2cnl]], [[2cnn|2cnn]], [[2cno|2cno]], [[2j30|2j30]], [[2j31|2j31]], [[2j32|2j32]], [[2j33|2j33]]</div></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2c2m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2m OCA], [https://pdbe.org/2c2m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c2m RCSB], [https://www.ebi.ac.uk/pdbsum/2c2m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c2m ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/CASP3_HUMAN 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.<ref>PMID:7596430</ref> <ref>PMID:21357690</ref> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Revision as of 13:01, 12 May 2021
Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor 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 PubMedAza-peptide Michael acceptors are a novel class of inhibitors that are potent and specific for caspases-2, -3, -6, -7, -8, -9, and -10. The second-order rate constants are in the order of 10(6) M(-1) s(-1). The aza-peptide Michael acceptor inhibitor 18t (Cbz-Asp-Glu-Val-AAsp-trans-CH=CH-CON(CH(2)-1-Naphth)(2) is the most potent compound and it inhibits caspase-3 with a k(2) value of 5620000 M(-1) s(-1). The inhibitor 18t is 13700, 190, 6.4, 594, 37500, and 173-fold more selective for caspase-3 over caspases-2, -6, -7, -8, -9, and -10, respectively. Aza-peptide Michael acceptors designed with caspase specific sequences are selective and do not show any cross reactivity with clan CA cysteine proteases such as papain, cathepsin B, and calpains. High-resolution crystal structures of caspase-3 and caspase-8 in complex with aza-peptide Michael acceptor inhibitors demonstrate the nucleophilic attack on C2 and provide insight into the selectivity and potency of the inhibitors with respect to the P1' moiety. Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10.,Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grutter MG, Powers JC J Med Chem. 2006 Sep 21;49(19):5728-49. PMID:16970398[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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