Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP

Protein Science : a Publication of the Protein Society
R AlmogP Van Roey

Abstract

The crystal structures of a deletion mutant of human thymidylate synthase (TS) and its ternary complex with dUMP and Tomudex have been determined at 2.0 A and 2.5 A resolution, respectively. The mutant TS, which lacks 23 residues near the amino terminus, is as active as the wild-type enzyme. The ternary complex is observed in the open conformation, similar to that of the free enzyme and to that of the ternary complex of rat TS with the same ligands. This is in contrast to Escherichia coli TS, where the ternary complex with Tomudex and dUMP is observed in the closed conformation. While the ligands interact with each other in identical fashion regardless of the enzyme conformation, they are displaced by about 1.0 A away from the catalytic cysteine in the open conformation. As a result, the covalent bond between the catalytic cysteine sulfhydryl and the base of dUMP, which is the first step in the reaction mechanism of TS and is observed in all ternary complexes of the E. coli enzyme, is not formed. This displacement results from differences in the interactions between Tomudex and the protein that are caused by differences in the environment of the glutamyl tail of the Tomudex molecule. Despite the absence of the closed conformati...Continue Reading

References

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Citations

Dec 15, 2012·Journal of Computer-aided Molecular Design·Adam Jarmuła, Wojciech Rode
Jan 17, 2004·Biochimica Et Biophysica Acta·Sondra H BergerLukasz Lebioda
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Dec 30, 2015·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Emmanuel Ndubuisi AgboPonnadurai Ramasami
Jul 2, 2009·Protein Science : a Publication of the Protein Society·Leslie L LovelaceLukasz Lebioda
May 21, 2013·Biochimica Et Biophysica Acta·Jenny Erales, Philip Coffino
Jun 19, 2008·Biochimica Et Biophysica Acta·Isabelle Jariel-EncontreMarc Piechaczyk
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Apr 15, 2006·Journal of Biochemical and Molecular Toxicology·Rogerio R Sotelo-MundoWilliam R Montfort
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Oct 26, 2021·The FEBS Journal·Sharon SpizzichinoFrancesca Cutruzzolà

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