1hw4

STRUCTURE OF THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS

spinqualitylabelsall models 1hw4, resolution 2.06Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1hw4 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: EDO, SO4 NonStd Res: CME Related: 1hw3 Activity: Thymidylate synthase, with EC number 2.1.1.45 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TYSY_HUMAN] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. 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 Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms. The emergence of resistance to the treatment is often related to the increased levels of TS in cancer cells, which have been linked to the elimination of TS binding to its own mRNA upon drug binding, a feedback regulatory mechanism, and/or to the increased stability to intracellular degradation of TS.drug complexes (versus unliganded TS). The active site loop of human TS (hTS) has a unique conformation resulted from a rotation by 180 degrees relative to its orientation in bacterial TSs. In this conformation, the enzyme must be inactive, because the catalytic cysteine is no longer positioned in the ligand-binding pocket. The ordered solvent structure obtained from high resolution crystallographic data (2.0 A) suggests that the inactive loop conformation promotes mRNA binding and intracellular degradation of the enzyme. This hypothesis is supported by fluorescence studies, which indicate that in solution both active and inactive forms of hTS are present. The binding of phosphate ion shifts the equilibrium toward the inactive conformation; subsequent dUMP binding reverses the equilibrium toward the active form. Thus, TS inhibition via stabilization of the inactive conformation should lead to less resistance than is observed with presently used drugs, which are analogs of its substrates, dUMP and CH(2)H(4)folate, and bind in the active site, promoting the active conformation. The presence of an extension at the N terminus of native hTS has no significant effect on kinetic properties or crystal structure. Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors.,Phan J, Steadman DJ, Koli S, Ding WC, Minor W, Dunlap RB, Berger SH, Lebioda L J Biol Chem. 2001 Apr 27;276(17):14170-7. Epub 2001 Jan 24. PMID:11278511 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase 3D structures

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