1mn7

NDP kinase mutant (H122G;N119S;F64W) in complex with aBAZTTPNDP kinase mutant (H122G;N119S;F64W) in complex with aBAZTTP

Structural highlights 1mn7 is a 2 chain structure with sequence from Dictyostelium discoideum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.15Å Ligands: , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NDKC_DICDI 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 Antiviral nucleoside analog therapies rely on their incorporation by viral DNA polymerases/reverse transcriptase leading to chain termination. The analogs (3'-deoxy-3'-azidothymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and other dideoxynucleosides) are sequentially converted into triphosphate by cellular kinases of the nucleoside salvage pathway and are often poor substrates of these enzymes. Nucleoside diphosphate (NDP) kinase phosphorylates the diphosphate derivatives of the analogs with an efficiency some 10(4) lower than for its natural substrates. Kinetic and structural studies of Dictyostelium and human NDP kinases show that the sugar 3'-OH, absent from all antiviral analogs, is required for catalysis. To improve the catalytic efficiency of NDP kinase on the analogs, we engineered several mutants with a protein OH group replacing the sugar 3'-OH. The substitution of Asn-115 in Ser and Leu-55 in His results in an NDP kinase mutant with an enhanced ability to phosphorylate antiviral derivatives. Transfection of the mutant enzyme in Escherichia coli results in an increased sensitivity to AZT. An x-ray structure at 2.15-A resolution of the Dictyostelium enzyme bearing the serine substitution in complex with the R(p)-alpha-borano-triphosphate derivative of AZT shows that the enhanced activity reflects an improved geometry of binding and a favorable interaction of the 3'-azido group with the engineered serine. Improving nucleoside diphosphate kinase for antiviral nucleotide analogs activation.,Gallois-Montbrun S, Schneider B, Chen Y, Giacomoni-Fernandes V, Mulard L, Morera S, Janin J, Deville-Bonne D, Veron M J Biol Chem. 2002 Oct 18;277(42):39953-9. Epub 2002 Aug 8. PMID:12171931 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Nucleoside diphosphate kinase 3D structures

spinqualitylabelsall models 1mn7, resolution 2.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image