2tsc

From Proteopedia

STRUCTURE, MULTIPLE SITE BINDING, AND SEGMENTAL ACCOMODATION IN THYMIDYLATE SYNTHASE ON BINDING D/UMP AND AN ANTI-FOLATE

PDB ID 2tsc

Drag the structure with the mouse to rotate

Structural highlights

2tsc is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.97Å
Ligands:	,
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.

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

The structure of Escherichia coli thymidylate synthase (TS) complexed with the substrate dUMP and an analogue of the cofactor methylenetetrahydrofolate was solved by multiple isomorphous replacement and refined at 1.97-A resolution to a residual of 18% for all data (16% for data greater than 2 sigma) for a highly constrained structure. All residues in the structure are clearly resolved and give a very high confidence in total correctness of the structure. The ternary complex directly suggests how methylation of dUMP takes place. C-6 of dUMP is covalently bound to gamma S of Cys-198(146) during catalysis, and the reactants are surrounded by specific hydrogen bonds and hydrophobic interactions from conserved residues. Comparison with the independently solved structure of unliganded TS reveals a large conformation change in the enzyme, which closes down to sequester the reactants and several highly ordered water molecules within a cavernous active center, away from bulk solvent. A second binding site for the quinazoline ring of the cofactor analogue was discovered by withholding addition of reducing agent during crystal storage. The chemical change in the protein is slight, and from difference density maps modification of sulfhydryls is not directly responsible for blockade of the primary site. The site, only partially overlapping with the primary site, is also surrounded by conserved residues and thus may play a functional role. The ligand-induced conformational change is not a domain shift but involves the segmental accommodation of several helices, beta-strands, and loops that move as units against the beta-sheet interface between monomers.

Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate.,Montfort WR, Perry KM, Fauman EB, Finer-Moore JS, Maley GF, Hardy L, Maley F, Stroud RM Biochemistry. 1990 Jul 31;29(30):6964-77. PMID:2223754^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Montfort WR, Perry KM, Fauman EB, Finer-Moore JS, Maley GF, Hardy L, Maley F, Stroud RM. Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folate. Biochemistry. 1990 Jul 31;29(30):6964-77. PMID:2223754