2C2Z: Crystal Structure Of Caspase-8 In Complex With Aza-peptide Michael Acceptor Inhibitor

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.
PDB ID: 2C2ZDownload
MMDB ID: 92258
PDB Deposition Date: 2005/10/2
Updated in MMDB: 2011/07
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2C2Z: hexameric; determined by author and by software (PQS)
Molecular Components in 2C2Z
Label Count Molecule
Proteins (6 molecules)
Caspase-8 P18 Subunit(Gene symbol: CASP8)
Molecule annotation
Caspase-8 P10 Subunit(Gene symbol: CASP8)
Molecule annotation
Aza-peptide Inhibitor (5s, 8R, 11s)-8-(2-carboxyethyl) -14-[4-(3,4-dihydroquinolin-1(2h)-yl)-4-oxobutanoyl] -11-[(1r)-1-hydroxyethyl]-5-(2-methylpropyl)-3,6,9,12-tetraoxo -1-phenyl-2-oxa-4,7,10,13,14-pentaazahexadecan-16-oic Acid
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB