4txc | pdb_00004txc

Crystal Structure of DAPK1 kinase domain in complex with a small molecule inhibitor

spinqualitylabelsall models 4txc, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4txc is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 38G, EDO Related: 2yak, 4pf4 Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DAPK1_HUMAN] Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell deaths signal, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript-selective translation inhibition. Isoform 2 cannot induce apoptosis but can induce membrane blebbing. Publication Abstract from PubMed A novel imidazo-pyramidazine inhibitor of DAPK1 that undergoes class-specific interactions and extends into the substrate recognition site has been identified. This inhibitor is a good starting point for the development of selective and potent inhibitors of DAPK1, with potential use against stroke and ischemia. Identification and Characterization of a Small-Molecule Inhibitor of Death-Associated Protein Kinase 1.,Wilbek TS, Skovgaard T, Sorrell FJ, Knapp S, Berthelsen J, Stromgaard K Chembiochem. 2014 Nov 7. doi: 10.1002/cbic.201402512. PMID:25382253 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Death-associated protein kinase

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