4gev | pdb_00004gev

E. coli thymidylate synthase Y209W variant in complex with substrate and a cofactor analog

spinqualitylabelsall models 4gev, resolution 1.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4gev is a 2 chain structure with sequence from Ecoli. This structure supersedes the now removed PDB entry 2g8m. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CB3, UMC NonStd Res: CXM Related: 2g8x, 2g8o, 2g86, 2g89, 2g8a, 2g8d 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 The role of protein flexibility in enzyme-catalyzed activation of chemical bonds is an evolving perspective in enzymology. Here we examine the role of protein motions in the hydride transfer reaction catalyzed by thymidylate synthase (TSase). Being remote from the chemical reaction site, the Y209W mutation of Escherichia coli TSase significantly reduces the protein activity, despite the remarkable similarity between the crystal structures of the wild-type and mutant enzymes with ligands representing their Michaelis complexes. The most conspicuous difference between these two crystal structures is in the anisotropic B-factors, which indicate disruption of the correlated atomic vibrations of protein residues in the mutant. This dynamically altered mutant allows a variety of small thiols to compete for the reaction intermediate that precedes the hydride transfer, indicating disruption of motions that preorganize the protein environment for this chemical step. Although the mutation causes higher enthalpy of activation of the hydride transfer, it only shows a small effect on the temperature dependence of the intrinsic KIE, suggesting marginal changes in the geometry and dynamics of the H-donor and -acceptor at the tunneling ready state. These observations suggest that the mutation disrupts the concerted motions that bring the H-donor and -acceptor together during the pre- and re-organization of the protein environment. The integrated structural and kinetic data allow us to probe the impact of protein motions on different time scales of the hydride transfer reaction within a complex enzymatic mechanism. A Remote Mutation Affects the Hydride Transfer by Disrupting Concerted Protein Motions in Thymidylate Synthase.,Wang Z, Abeysinghe T, Finer-Moore JS, Stroud RM, Kohen A J Am Chem Soc. 2012 Oct 15. PMID:23034004 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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