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PDBsum entry 2c2k
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Hydrolase/hydrolase inhibitor
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PDB id
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2c2k
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And evaluation of aza-Peptide michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, And -10.
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Authors
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O.D.Ekici,
Z.Z.Li,
A.J.Campbell,
K.E.James,
J.L.Asgian,
J.Mikolajczyk,
G.S.Salvesen,
R.Ganesan,
S.Jelakovic,
M.G.Grütter,
J.C.Powers.
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Ref.
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J Med Chem, 2006,
49,
5728-5749.
[DOI no: ]
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PubMed id
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Abstract
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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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