9inw

Crystal structure of DAPK1 in complex with compound 9

spinqualitylabelsall models 9inw, resolution 1.52Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9inw is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.52Å Ligands: A1L2V, SO4 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 Death-associated protein kinase 1 (DAPK1) is a phosphotransferase in the serine/threonine kinase family. Inhibiting DAPK1 is expected to be beneficial in treating Alzheimer's disease and protecting neuronal cells during cerebral ischemia. In this study, we demonstrated that the natural chalcone isoliquiritigenin inhibits DAPK1 in an ATP-competitive manner, and we synthesized halogen derivatives to amplify the inhibitory effect. Among the compounds tested, the chlorine, bromine, and iodine derivatives exhibited high DAPK1 inhibitory activity and binding affinity. Crystal structure analysis revealed that this improvement is attributable to the halogen atoms fitting well into the hydrophobic pocket formed by I77, L93, and I160. In particular, the chlorine derivative showed a significant enthalpic contribution to the interaction with DAPK1, suggesting its potential as a primary compound for new DAPK1 inhibitors. Discovery and optimization of isoliquiritigenin as a death-associated protein kinase 1 inhibitor.,Yokoyama T, Hisatomi K, Oshima S, Tanaka I, Okada T, Toyooka N Eur J Med Chem. 2024 Sep 4;279:116836. doi: 10.1016/j.ejmech.2024.116836. PMID:39243455 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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