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2CNN

Crystal structures of caspase-3 in complex with aza-peptide epoxide inhibitors.

Summary for 2CNN
Entry DOI10.2210/pdb2cnn/pdb
Related1CP3 1GFW 1I3O 1NME 1NMQ 1NMS 1PAU 1QX3 1RE1 1RHJ 1RHK 1RHM 1RHQ 1RHR 1RHU 2C1E 2C2K 2C2M 2C2O 2CDR 2CJX 2CJY 2CNK 2CNL 2CNO
Related PRD IDPRD_000671
DescriptorCaspase-3, AZA-PEPTIDE EXPOXIDE, ... (4 entities in total)
Functional Keywordsthiol protease, phosphorylation, cysteine-protease, protease-inhibitor complex, protease, epoxides, tetramer, apoptosis, aza-peptide, epoxysuccinyl, ice, yama, cpp32, clan cd, aza-asp, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
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Cellular locationCytoplasm: P42574 2CNN
Total number of polymer chains3
Total formula weight29483.91
Authors
Ganesan, R.,Jelakovic, S.,Campbell, A.J.,Li, Z.Z.,Asgian, J.L.,Powers, J.C.,Grutter, M.G. (deposition date: 2006-05-22, release date: 2007-05-22, Last modification date: 2024-11-06)
Primary citationGanesan, R.,Jelakovic, S.,Campbell, A.J.,Li, Z.Z.,Asgian, J.L.,Powers M, J.C.,Gruetter, G.
Exploring the S4 and S1 Prime Subsite Specificities in Caspase-3 with Aza-Peptide Epoxide Inhibitors
Biochemistry, 45:9059-, 2006
Cited by
PubMed Abstract: 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.
PubMed: 16866351
DOI: 10.1021/BI060364P
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.7 Å)
Structure validation

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数据于2024-11-06公开中

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