3R7N

Caspase-2 bound with two copies of Ac-DVAD-CHO

Summary for 3R7N

• Entry DOI: 10.2210/pdb3r7n/pdb
• Related: 3R5J 3R6G 3R6L 3R7B 3R7S
• Related PRD ID: PRD_001052
• Descriptor: Caspase-2 subunit p18, Caspase-2 subunit p12, Peptide Inhibitor (ACE)DVAD-CHO, ... (4 entities in total)
• Functional Keywords: hydrolase, apoptosis, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 62885.91

Authors

Tang, Y.,Wells, J.,Arkin, M. (deposition date: 2011-03-22, release date: 2011-07-27, Last modification date: 2012-12-12)

Primary citation

Tang, Y.,Wells, J.A.,Arkin, M.R.
Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis.
J.Biol.Chem., 286:34147-34154, 2011

PubMed Abstract: Caspase-2, the most evolutionarily conserved member in the human caspase family, may play important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression. In biochemical assays, caspase-2 uniquely prefers a pentapeptide (such as VDVAD) rather than a tetrapeptide, as required for efficient cleavage by other caspases. We investigated the molecular basis for pentapeptide specificity using peptide analog inhibitors and substrates that vary at the P5 position. We determined the crystal structures of apo caspase-2, caspase-2 in complex with peptide inhibitors VDVAD-CHO, ADVAD-CHO, and DVAD-CHO, and a T380A mutant of caspase-2 in complex with VDVAD-CHO. Two residues, Thr-380 and Tyr-420, are identified to be critical for the P5 residue recognition; mutation of the two residues reduces the catalytic efficiency by about 4- and 40-fold, respectively. The structures also provide a series of snapshots of caspase-2 in different catalytic states, shedding light on the mechanism of capase-2 activation, substrate binding, and catalysis. By comparing the apo and inhibited caspase-2 structures, we propose that the disruption of a non-conserved salt bridge between Glu-217 and the invariant Arg-378 is important for the activation of caspase-2. These findings broaden our understanding of caspase-2 substrate specificity and catalysis.

PubMed: 21828056
DOI: 10.1074/jbc.M111.247627

Experimental method

X-RAY DIFFRACTION (2.33 Å)