2C1E

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

Summary for 2C1E

• Entry DOI: 10.2210/pdb2c1e/pdb
• Related: 1CP3 1GFW 1I3O 1NME 1NMQ 1NMS 1PAU 1QX3 1RE1 1RHJ 1RHK 1RHM 1RHQ 1RHR 1RHU 2C2K 2C2M 2C2O 2CDR 2CJX 2CJY 2CNK 2CNL 2CNN 2CNO 2J30 2J31 2J32 2J33
• Related PRD ID: PRD_000330
• Descriptor: CASPASE-3 SUBUNIT P17, CASPASE-3 SUBUNIT P12, AZA-PEPTIDE INHIBITOR (5S, 8R, 11S)-8-(2-CARBOXYETHYL)-5-(CARBOXYMETHYL)-14-(4-ETHOXY-4-OXOBUTANOYL)-11-(1-METHYLETHYL)-3,6,9,12-TETRAOXO-1-PHENYL-2-OXA-4,7,10,13,14-PENTAAZAHEXADECAN -16-OIC ACID, ... (4 entities in total)
• Functional Keywords: apoptosis, hydrolase-hydrolase inhibitor complex, cysteine-protease, thiol protease, zymogen, cpp32, yama, aza-peptide, michael acceptor, aza-asp, clan cd, hydrolase/hydrolase inhibitor
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P42574 P42574
• Total number of polymer chains: 3
• Total formula weight: 29335.70

Authors

Grutter, M.G. (deposition date: 2005-09-14, release date: 2006-09-20, Last modification date: 2023-11-15)

Primary citation

Ekici, O.D.,Li, Z.Z.,Campbell, A.J.,James, K.E.,Asgian, J.L.,Mikolajczyk, J.,Salvesen, G.S.,Ganesan, R.,Jelakovic, S.,Grutter, M.G.,Powers, J.C.
Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Selective and Potent Inhibitors of Caspases-2, -3, -6, -7, -8, -9, and - 10.
J.Med.Chem., 49:5728-, 2006

PubMed Abstract: 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.

PubMed: 16970398
DOI: 10.1021/JM0601405

Experimental method

X-RAY DIFFRACTION (1.77 Å)