4jlk | pdb_00004jlk

Human dCK C4S-S74E mutant in complex with UDP and the F2.2.1 inhibitoR (2-[({2-[3-(2-FLUOROETHOXY)-4-METHOXYPHENYL]-5-METHYL-1,3-THIAZOL-4-YL}METHYL)SULFANYL]PYRIMIDINE-4,6-DIAMINE)

spinqualitylabelsall models 4jlk, resolution 1.89Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4jlk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1NO, UDP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DCK_HUMAN Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based on the chirality of the substrate. It is also an essential enzyme for the phosphorylation of numerous nucleoside analogs widely employed as antiviral and chemotherapeutic agents. Publication Abstract from PubMed Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = approximately 1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy. Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.,Murphy JM, Armijo AL, Nomme J, Lee CH, Smith QA, Li Z, Campbell DO, Liao HI, Nathanson DA, Austin WR, Lee JT, Darvish R, Wei L, Wang J, Su Y, Damoiseaux R, Sadeghi S, Phelps ME, Herschman HR, Czernin J, Alexandrova AN, Jung ME, Lavie A, Radu CG J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y. Epub 2013 Aug, 15. PMID:23947754 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Deoxycytidine kinase 3D structures

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