2CNN: Crystal Structures Of Caspase-3 In Complex With Aza-peptide Epoxide Inhibitors

Caspase-3 is a prototypic executioner caspase that plays a central role in apoptosis. Aza-peptide epoxides are a novel class of irreversible inhibitors that are highly specific for clan CD cysteine proteases. The five crystal structures of caspase-3-aza-peptide epoxide inhibitor complexes reported here reveal the structural basis for the mechanism of inhibition and the specificities at the S1' and the S4 subsites. Unlike the clan CA cysteine proteases, the catalytic histidine in caspase-3 plays a critical role during protonation and subsequent ring opening of the epoxide moiety and facilitates the nucleophilic attack by the active site cysteine. The nucleophilic attack takes place on the C3 carbon atom of the epoxide and results in an irreversible alkylation of the active site cysteine residue. A favorable network of hydrogen bonds involving the oxyanion hole, catalytic histidine, and the atoms in the prime site of the inhibitor enhance the binding affinity and specificity of the aza-peptide epoxide inhibitors toward caspase-3. The studies also reveal that subtle movements of the N-terminal loop of the beta-subunit occur when the P4 Asp is replaced by a P4 Ile, whereas the N-terminal loop and the safety catch Asp179 are completely disordered when the P4 Asp is replaced by P4 Cbz group.
PDB ID: 2CNNDownload
MMDB ID: 103870
PDB Deposition Date: 2006/5/22
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 2CNN: hexameric; determined by author and by software (PQS)
Molecular Components in 2CNN
Label Count Molecule
Proteins (6 molecules)
Caspase-3 Subunit P17(Gene symbol: CASP3)
Molecule annotation
Caspase-3 Subunit P12(Gene symbol: CASP3)
Molecule annotation
Aza-peptide Expoxide
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB