Montfort TS

Montfort Lab - Thymidylate Synthase

Our recent studies of thymidylate synthase (TS) have addressed the role of ligand-induced conformational changes in catalysis, the atomic details of the TS catalytic mechanism, and the means by which the best inhibitors and anticancer drugs targeted to TS carry out their functions. Multiple structures have been determined with TS bound to substrates and inhibitors, allowing us to model all steps in catalysis by TS. One conclusion from these studies is that TS makes use of an extensive conformational change to bind the low energy "flat" conformer of cofactor methylenetetrahydrofolate, and convert it to a high energy "bent" conformer that is appropriate for initiating catalysis.

Abstracts from recent papers and molecular graphics displays of recent structures.

R.R. Sotelo-Mundo, J. Ciesla, J.M. Dzik, W. Rode, F. Maley, G.F. Maley, L.W. Hardy & W.R. Montfort. Crystal Structures of Rat Thymidylate Synthase Inhibited by Tomudex, a Potent Anticancer Drug. Biochemistry (1999), 38:1087-1094.

A.P. Lobo, M.G. Nair, L. Changchien, A. Weichsel, W.R. Montfort, F. Maley. Mode of Action of Site-Directed Irreversible Folate Analogue Inhibitors of Thymidylate Synthase. Biochemistry (1998), 37:4535-4542.

P. Strop, L. Chanchien, F. Maley, & W.R. Montfort. Crystal structures of a marginally active thymidylate synthase mutant, Arg 126 -> Glu. Protein Science (1997), 6:2504-2511.

W.R. Montfort & A. Weichsel. Thymidylate Synthase: Structure, Inhibition, and Strained Conformations During Catalysis. Pharmacology & Therapeutics (1997), 76:29-43.

D.C. Hyatt, F. Maley, and W.R. Montfort. Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of E. coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate. Biochemistry (1997), 36:4585-4594.

Molecular Graphics

A. Weichsel and W.R. Montfort. Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843U89. Nature Structural Biology (1995), 2:1095-1101.

D. M. Voeller, T. Takechi, R. E. Turner, G. F. Maley, F. Maley, W. R. Montfort, C. J. Allegra, and E. Chu. Characterization of a Specific Interaction Between Escherichia Coli Thymidylate Synthase and Escherichia Coli Thymidylate Synthase mRNA. Nucleic Acids Res. (1995), 23:869-875.

A. Weichsel, W.R. Montfort, J. Ciesla, and F. Maley. Promotion of Purine Nucleotide Binding to Thymidylate Synthase by a Potent Folate Analogue Inhibitor, 1843U89. Proc. Natl. Acad. Sci. USA. (1995), 92:3493-3497.

Montfort Lab - Thymidylate Synthase

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