2c2k: Difference between revisions

Revision as of 07:12, 9 March 2017

Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.

Structural highlights

2c2k is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:	AA1, PHQ
Related:	1cp3, 1gfw, 1i3o, 1nme, 1nmq, 1nms, 1pau, 1qx3, 1re1, 1rhj, 1rhk, 1rhm, 1rhq, 1rhr, 1rhu, 2c1e, 2c2m, 2c2o, 2cdr, 2cjx, 2cjy, 2cnk, 2cnl, 2cnn, 2cno, 2j30, 2j31, 2j32, 2j33
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

Aza-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.

References

↑ Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:https://dx.doi.org/10.1038/376037a0
↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
↑ Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grutter MG, Powers JC. Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10. J Med Chem. 2006 Sep 21;49(19):5728-49. PMID:16970398 doi:https://dx.doi.org/10.1021/jm0601405

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OCA

[1] Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:https://dx.doi.org/10.1038/376037a0

[2] Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461

[3] Ekici OD, Li ZZ, Campbell AJ, James KE, Asgian JL, Mikolajczyk J, Salvesen GS, Ganesan R, Jelakovic S, Grutter MG, Powers JC. Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10. J Med Chem. 2006 Sep 21;49(19):5728-49. PMID:16970398 doi:https://dx.doi.org/10.1021/jm0601405

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-==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.==
 <StructureSection load='2c2k' size='340' side='right' caption='[[2c2k]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2c2k]] is a 3 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=2C2K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2C2K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2c2k]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C2K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2C2K FirstGlance]. <br>
 </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AA1:[1-(4-ETHOXY-4-OXOBUTANOYL)HYDRAZINO]ACETIC+ACID'>AA1</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]], [[2c2m|2c2m]], [[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='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=2c2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2k OCA], [http://pdbe.org/2c2k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2c2k RCSB], [http://www.ebi.ac.uk/pdbsum/2c2k 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=2c2k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2k OCA], [http://pdbe.org/2c2k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2c2k RCSB], [http://www.ebi.ac.uk/pdbsum/2c2k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2c2k ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 35: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
 [[Category: Asgian, J L]]
 [[Category: Campbell, A J]]

2c2k: Difference between revisions

Revision as of 07:12, 9 March 2017

Crystal structures of caspase-3 in complex with aza-peptide Michael acceptor inhibitors.

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

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