1zm7

Crystal structure of D. melanogaster deoxyribonucleoside kinase mutant N64D in complex with dTTP

spinqualitylabelsall models 1zm7, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1zm7 is a 4 chain structure with sequence from Drosophila melanogaster. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.2Å Ligands: MG, TTP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DNK_DROME Deoxyribonucleoside kinase that has a broad specificity phosphorylating thymidine, deoxyadenosine, deoxycytidine and deoxyguanosine. Specificity is higher for pyrimidine nucleosides. Several anti-viral and anti-cancer nucleoside analogs are also efficiently phosphorylated. 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 The Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK) double mutant N45D/N64D was identified during a previous directed evolution study. This mutant enzyme had a decreased activity towards the natural substrates and decreased feedback inhibition with dTTP, whereas the activity with 3'-modified nucleoside analogs like 3'-azidothymidine (AZT) was nearly unchanged. Here, we identify the mutation N64D as being responsible for these changes. Furthermore, we crystallized the mutant enzyme in the presence of one of its substrates, thymidine, and the feedback inhibitor, dTTP. The introduction of the charged Asp residue appears to destabilize the LID region (residues 167-176) of the enzyme by electrostatic repulsion and no hydrogen bond to the 3'-OH is made in the substrate complex by Glu172 of the LID region. This provides a binding space for more bulky 3'-substituents like the azido group in AZT but influences negatively the interactions between Dm-dNK, substrates and feedback inhibitors based on deoxyribose. The detailed picture of the structure-function relationship provides an improved background for future development of novel mutant suicide genes for Dm-dNK-mediated gene therapy. Structural basis for the changed substrate specificity of Drosophila melanogaster deoxyribonucleoside kinase mutant N64D.,Welin M, Skovgaard T, Knecht W, Zhu C, Berenstein D, Munch-Petersen B, Piskur J, Eklund H FEBS J. 2005 Jul;272(14):3733-42. PMID:16008571 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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