3r5j | pdb_00003r5j

Crystal structure of active caspase-2 bound with Ac-ADVAD-CHO

spinqualitylabelsall models 3r5j, resolution 1.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3r5j is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. NonStd Res: ACE, ASA Related: 3r7n, 3r7b, 3r6l, 3r6g, 3r7s Gene: CASP2, ICH1, NEDD2 (HUMAN) Activity: Caspase-2, with EC number 3.4.22.55 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CASP2_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival. Publication Abstract from PubMed 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. Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis.,Tang Y, Wells JA, Arkin MR J Biol Chem. 2011 Sep 30;286(39):34147-54. Epub 2011 Aug 2. PMID:21828056 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Caspase

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