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Báo cáo khoa học: Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme

Thymidine kinases have been found in most organisms, from viruses and bacteria to mammals.Ureaplasma urealyticum(parvum), which belongs to the class of cell-wall-lacking Mollicutes, has no de novosynthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus, thymi-dine kinase (Uu-TK) is the key enzyme in dTTP synthesis. | ềFEBS Journal Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme Urszula Kosinska1 Cecilia Carnrot2 Staffan Eriksson2 Liya Wang2 and Hans Eklund1 1 Department of Molecular Biology Swedish University of AgriculturalSciences Uppsala BiomedicalCentre Sweden 2 Department of Molecular Biosciences Swedish University of AgriculturalSciences Uppsala BiomedicalCentre Sweden Keywords bacterial crystallography deoxythymidine nucleoside analogues thymidine kinase Correspondence H. Eklund Department of Molecular Biology Swedish University of Agricultural Sciences PO Box 590 BiomedicalCentre S-751 24 Uppsala Sweden Fax 46 18 53 69 71 Tel 46 18 4754559 E-mail hasse@xray.bmc.uu.se Note These authors contributed equally to this work. Received 22 August 2005 revised 14 October 2005 accepted 21 October 2005 doi 10.1111 j.1742-4658.2005.05030.x Thymidine kinases have been found in most organisms from viruses and bacteria to mammals. Ureaplasma urealyticum parvum which belongs to the class of cell-wall-lacking Mollicutes has no de novo synthesis of DNA precursors and therefore has to rely on the salvage pathway. Thus thymidine kinase Uu-TK is the key enzyme in dTTP synthesis. Recently the 3D structure of Uu-TK was determined in a feedback inhibitor complex demonstrating that a lasso-like loop binds the thymidine moiety of the feedback inhibitor by hydrogen bonding to main-chain atoms. Here the structure with the substrate deoxythymidine is presented. The substrate binds similarly to the deoxythymidine part of the feedback inhibitor and the lasso-like loop binds the base and deoxyribose moieties as in the complex determined previously. The catalytic base Glu97 has a different position in the substrate complex from that in the complex with the feedback inhibitor having moved in closer to the 5 -OH of the substrate to form a hydrogen bond. The phosphorylation of and inhibition by several nucleoside