PDBsum entry 2c1e

Hydrolase/hydrolase inhibitor

PDB id: 2c1e

Contents

Protein chains

147 a.a. *

103 a.a. *

Ligands

PHQ-ASP-GLU-VAL-AA1

Waters ×414

* Residue conservation analysis

PDB id:

2c1e

Name:

Hydrolase/hydrolase inhibitor

Title:

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

Structure:

Caspase-3 subunit p17. Chain: a. Fragment: alpha subunit, residues 29-175. Synonym: casp-3, apopain, cysteine protease cpp32, yama protein, cpp- 32, srebp cleavage activity 1, sca-1. Engineered: yes. Caspase-3 subunit p12. Chain: b. Fragment: beta subunit, residues 176-277.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Biol. unit:

Hexamer (from PDB file)

Resolution:

1.77Å R-factor: 0.163 R-free: 0.188

Authors:

M.G.Grutter

Key ref:

O.D.Ekici et al. (2006). 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, 5728-5749. PubMed id: 16970398 DOI: 10.1021/jm0601405

Date:

14-Sep-05 Release date: 20-Sep-06

Protein chain

P42574  (CASP3_HUMAN) -  Caspase-3 from Homo sapiens

Seq: 277 a.a.

Struc: 147 a.a.

Protein chain

P42574  (CASP3_HUMAN) -  Caspase-3 from Homo sapiens

Seq: 277 a.a.

Struc: 103 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.22.56 - caspase-3.

DOI no: 10.1021/jm0601405

J Med Chem 49:5728-5749 (2006)

PubMed id: 16970398

Design, synthesis, and evaluation of aza-peptide Michael acceptors as selective and potent inhibitors of caspases-2, -3, -6, -7, -8, -9, and -10.

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.

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.