4knz | pdb_00004knz

Thymidylate synthase ternary complex with dUMP AND CB3717

spinqualitylabelsall models 4knz, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4knz is a 2 chain structure with sequence from Ecoli. This structure supersedes the now removed PDB entries 4iw5 and 2g8o. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CB3, NA, UMC NonStd Res: CXM Related: 4gev Gene: b2827, JW2795, thyA (ECOLI) Activity: Thymidylate synthase, with EC number 2.1.1.45 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [TYSY_ECOLI] Provides the sole de novo source of dTMP for DNA biosynthesis. This protein also binds to its mRNA thus repressing its own translation. Publication Abstract from PubMed Thymidylate synthase (TSase) produces the sole intracellular de novo source of thymidine (i.e. the DNA base T) and thus is a common target for antibiotic and anticancer drugs. Mg2+ has been reported to affect TSase activity, but the mechanism of this interaction has not been investigated. Here we show that Mg2+ binds to the surface of Escherichia coli TSase and affects the kinetics of hydride transfer at the interior active site (16 A away). Examination of the crystal structures identifies a Mg2+ near the glutamyl moiety of the folate cofactor, providing the first structural evidence for Mg2+ binding to TSase. The kinetics and NMR relaxation experiments suggest that the weak binding of Mg2+ to the protein surface stabilizes the closed conformation of the ternary enzyme complex and reduces the entropy of activation on the hydride transfer step. Mg2+ accelerates the hydride transfer by ca. 7-fold but does not affect the magnitude or temperature-dependence of the intrinsic kinetic isotope effect. These results suggest that Mg2+ facilitates the protein motions that bring the hydride donor and acceptor together, but it does not change the tunneling ready state of the hydride transfer. These findings highlight how variations in cellular Mg2+ concentration can modulate enzyme activity through long-range interactions in the protein, rather than binding at the active site. The interaction of Mg2+ with the glutamyl-tail of the folate cofactor and nonconserved residues of bacterial TSase may assist in designing antifolates with poly-glutamyl substitutes as species-specific antibiotic drugs. Mg2+ binds to the surface of thymidylate synthase and affects hydride transfer at the interior active site.,Wang Z, Sapienza PJ, Abeysinghe T, Luzum C, Lee AL, Finer-Moore JS, Stroud RM, Kohen A J Am Chem Soc. 2013 Apr 23. PMID:23611499 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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