1nn0

Crystal structure of human thymidylate kinase with ddTMP and ADP

spinqualitylabelsall models 1nn0, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1nn0 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2DT, ADP, MG Gene: DTYMK OR TYMK OR TMPK OR CDC8 (HUMAN) Activity: dTMP kinase, with EC number 2.7.4.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [KTHY_HUMAN] Catalyzes the conversion of dTMP to dTDP. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise phosphorylation to their triphosphate form to become therapeutically active. In many cases it is this activation pathway that largely determines the efficacy of the drug. To gain further understanding of the determinants for efficient conversion by the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates, we solved the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with steady-state kinetic data, our structures shed light on the effect of 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on the catalytic rate. We observe a direct correlation between the rate of phosphorylation of an NMP and its ability to induce a closing of the enzyme's phosphate-binding loop (P-loop). Our results show the drastic effects that slight modifications of the substrates exert on the enzyme's conformation and, hence, activity and suggest the type of substitutions that are compatible with efficient phosphorylation by TMPK. Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds.,Ostermann N, Segura-Pena D, Meier C, Veit T, Monnerjahn C, Konrad M, Lavie A Biochemistry. 2003 Mar 11;42(9):2568-77. PMID:12614151 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate kinase 3D structures

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