2c1e: Difference between revisions

Revision as of 17:43, 21 February 2008

CRYSTAL STRUCTURES OF CASPASE-3 IN COMPLEX WITH AZA-PEPTIDE MICHAEL ACCEPTOR INHIBITORS.

OverviewOverview

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 StructureAbout this Structure

2C1E is a Protein complex structure of sequences from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

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 Thu Feb 21 16:43:50 2008

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OCA

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-[[Image:2c1e.gif|left|200px]]<br />
+[[Image:2c1e.gif|left|200px]]<br /><applet load="2c1e" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="2c1e" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="2c1e, resolution 1.77&Aring;" />
 '''CRYSTAL STRUCTURES OF CASPASE-3 IN COMPLEX WITH AZA-PEPTIDE MICHAEL ACCEPTOR INHIBITORS.'''<br />
 ==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.
 ==About this Structure==
-C1E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PHQ and AA1 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2C1E OCA].
+C1E is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=PHQ:'>PHQ</scene> and <scene name='pdbligand=AA1:'>AA1</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C1E OCA].
 ==Reference==
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 [[Category: Homo sapiens]]
 [[Category: Protein complex]]
-[[Category: Grutter, M.G.]]
+[[Category: Grutter, M G.]]
 [[Category: AA1]]
 [[Category: PHQ]]
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 [[Category: zymogen]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:09:32 2007''
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