2DKO

Extended substrate recognition in caspase-3 revealed by high resolution X-ray structure analysis

Summary for 2DKO

• Entry DOI: 10.2210/pdb2dko/pdb
• Related PRD ID: PRD_000277
• Descriptor: Caspase-3, PHQ-ASP-GLU-VAL-ASP-CHLOROMETHYLKETONE, ... (4 entities in total)
• Functional Keywords: low barrier hydrogen bond, caspase, drug design, radiation damage, tetrahedral intermediate, protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P42574 P42574
• Total number of polymer chains: 3
• Total formula weight: 29167.98

Authors

Mittl, P.R.E.,Ganesan, R.,Jelakovic, S.,Grutter, M.G. (deposition date: 2006-04-12, release date: 2006-07-04, Last modification date: 2024-10-30)

Primary citation

Ganesan, R.,Mittl, P.R.E.,Jelakovic, S.,Grutter, M.G.
Extended Substrate Recognition in Caspase-3 Revealed by High Resolution X-ray Structure Analysis
J.Mol.Biol., 359:1378-1388, 2006

PubMed Abstract: Caspases are cysteine proteases involved in the signalling cascades of programmed cell death in which caspase-3 plays a central role, since it propagates death signals from intrinsic and extrinsic stimuli to downstream targets. The atomic resolution (1.06 Angstroms) crystal structure of the caspase-3 DEVD-cmk complex reveals the structural basis for substrate selectivity in the S4 pocket. A low-barrier hydrogen bond is observed between the side-chains of the P4 inhibitor aspartic acid and Asp179 of the N-terminal tail of the symmetry related p12 subunit. Site-directed mutagenesis of Asp179 confirmed the significance of this residue in substrate recognition. In the 1.06 Angstroms crystal structure, a radiation damage induced rearrangement of the inhibitor methylketone moiety was observed. The carbon atom that in a substrate would represent the scissile peptide bond carbonyl carbon clearly shows a tetrahedral coordination and resembles the postulated tetrahedral intermediate of the acylation reaction.

PubMed: 16787777
DOI: 10.1016/j.jmb.2006.04.051

Experimental method

X-RAY DIFFRACTION (1.06 Å)