2c2z
From Proteopedia
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|PDB= 2c2z |SIZE=350|CAPTION= <scene name='initialview01'>2c2z</scene>, resolution 1.95Å | |PDB= 2c2z |SIZE=350|CAPTION= <scene name='initialview01'>2c2z</scene>, resolution 1.95Å | ||
|SITE= <scene name='pdbsite=AC1:Dtd+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Dtd+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand=DTD:DITHIANE DIOL'>DTD</scene> | + | |LIGAND= <scene name='pdbligand=DTD:DITHIANE+DIOL'>DTD</scene>, <scene name='pdbligand=MX5:{1-[4-(3,4-DIHYDROQUINOLIN-1(2H)-YL)-4-OXOBUTANOYL]HYDRAZINO}ACETIC+ACID'>MX5</scene>, <scene name='pdbligand=PHQ:FORMIC+ACID+BENZYL+ESTER'>PHQ</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2c2z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c2z OCA], [http://www.ebi.ac.uk/pdbsum/2c2z PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2c2z RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
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| - | ==Disease== | ||
| - | Known diseases associated with this structure: Autoimmune lymphoproliferative syndrome, type IIB OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Breast cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Hepatocellular carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]], Lung cancer, protection against OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601763 601763]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Powers, J C.]] | [[Category: Powers, J C.]] | ||
[[Category: Salvesen, G S.]] | [[Category: Salvesen, G S.]] | ||
| - | [[Category: DTD]] | ||
[[Category: apoptosis]] | [[Category: apoptosis]] | ||
[[Category: aza-asp]] | [[Category: aza-asp]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:15:32 2008'' |
Revision as of 23:15, 30 March 2008
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| , resolution 1.95Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF CASPASE-8 IN COMPLEX WITH AZA-PEPTIDE MICHAEL ACCEPTOR INHIBITOR
Overview
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.
About this Structure
2C2Z is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Mon Mar 31 02:15:32 2008
Categories: Homo sapiens | Single protein | Asgian, J L. | Campbell, A J. | Ekici, O D. | Ganesan, R. | Gruetter, M G. | James, K E. | Jelakovic, S. | Li, Z Z. | Mikolajczyk, J. | Powers, J C. | Salvesen, G S. | Apoptosis | Aza-asp | Aza-peptide | Clan cd | Complex (protease-inhibitor) | Cpp32 | Cysteine-protease | Hydrolase | Ice | Michael acceptor | Tetramer | Thiol protease | Yama | Zymogen
