2bbq
STRUCTURAL BASIS FOR RECOGNITION OF POLYGLUTAMYL FOLATES BY THYMIDYLATE SYNTHASE
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OverviewOverview
Thymidylate synthase (TS) catalyzes the final step in the de novo, synthesis of thymidine. In vivo TS binds a polyglutamyl cofactor, polyglutamyl methylenetetrahydrofolate (CH2-H4folate), which serves as a, carbon donor. Glutamate residues on the cofactor contribute as much as 3.7, kcal to the interaction between the cofactor, substrate, and enzyme., Because many ligand/receptor interactions appear to be driven largely by, hydrophobic forces, it is surprising that the addition of hydrophilic, soluble groups such as glutamates increases the affinity of the cofactor, for TS. The structure of a polyglutamyl cofactor analog bound in ternary, complex with deoxyuridine monophosphate (dUMP) and Escherichia coli TS, reveals how the polyglutamyl moiety is positioned in TS and accounts in a, qualitative way for the binding contributions of the different individual, glutamate residues. The polyglutamyl moiety is not rigidly fixed by its, interaction with the protein except for the first glutamate residue, nearest the p-aminobenzoic acid ring of folate. Each additional glutamate, is progressively more disordered than the previous one in the chain. The, position of the second and third glutamate residues on the protein surface, suggests that the polyglutamyl binding site could be utilized by a new, family of inhibitors that might fill the binding area more effectively, than polyglutamate.
About this StructureAbout this Structure
2BBQ is a Single protein structure of sequence from Escherichia coli with UMP and PFG as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for recognition of polyglutamyl folates by thymidylate synthase., Kamb A, Finer-Moore J, Calvert AH, Stroud RM, Biochemistry. 1992 Oct 20;31(41):9883-90. PMID:1390771
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