6f6z | pdb_00006f6z

Mouse Thymidylate Synthase Cocrystallized with N(4)OHdCMP and Soaked in Methylenetetrahydrofolate

spinqualitylabelsall models 6f6z, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6f6z is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NOH, TGQ Gene: Tyms (LK3 transgenic mice) Activity: Thymidylate synthase, with EC number 2.1.1.45 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TYSY_MOUSE] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway (By similarity). Publication Abstract from PubMed Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N(4)-hydroxy-dCMP (N(4)-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N(4)-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N(4)-OH-dCMP and N(5,10)-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N(4)-OH-dCMP and N(5,10)-methylenetetrahdrofolate. The crystal structure of the mouse TS-N(4)-OH-dCMP complex soaked with N(5,10)-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer. Molecular Mechanism of Thymidylate Synthase Inhibition by N(4)-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies.,Maj P, Jarmula A, Wilk P, Prokopowicz M, Rypniewski W, Zielinski Z, Dowiercial A, Bzowska A, Rode W Int J Mol Sci. 2021 Apr 30;22(9). pii: ijms22094758. doi: 10.3390/ijms22094758. PMID:33946210 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Thymidylate synthase 3D structures

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