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Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug.

Sotelo-Mundo RR, Ciesla J, Dzik JM, Rode W, Maley F, Maley GF, Hardy LW, Montfort WR
Biochemistry 38 1087-94 (1999)
Cited: 22 times
EuropePMC logo PMID: 9894005

Abstract

Two crystal structures of rat thymidylate synthase (TS) complexed with dUMP and the anticancer drug Tomudex (ZD1694) have been determined to resolutions of 3.3 and 2.6 A. Tomudex is one of several new antifolates targeted to TS and the first to be approved for clinical use. The structures represent the first views of any mammalian TS bound to ligands and suggest that the rat protein undergoes a ligand-induced conformational change similar to that of the Escherichia coli protein. Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen on binding to E. coli TS, resulting in inhibitor atoms that differ in position by more than 1.5 A. Several species-specific differences in sequence may be the reason for this. Phe 74 shifts to a new position in the rat complex and is in van der Waals contact with the inhibitor, while in the E. coli protein the equivalent amino acid (His 51) hydrogen bonds to the glutamate portion of the inhibitor. Amino acids Arg 101, Asn 106, and Met 305 make no contacts with the inhibitor in the open conformation, unlike the equivalent residues in the E. coli protein (Thr 78, Trp 83, and Val 262). dUMP binding is similar in both proteins, except that there is no covalent adduct to the active site cysteine (Cys 189) in the rat structures. Two insertions in the rat protein are clearly seen, but the N-termini (residues 1-20) and C-termini (residues 301-307) are disordered in both crystal forms.

Articles - 2tsr mentioned but not cited (2)

  1. Crystal structure of mouse thymidylate synthase in tertiary complex with dUMP and raltitrexed reveals N-terminus architecture and two different active site conformations. Dowierciał A, Wilk P, Wilk P, Rypniewski W, Rode W, Jarmuła A. Biomed Res Int 2014 945803 (2014)
  2. Molecular Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies. Maj P, Jarmuła A, Wilk P, Prokopowicz M, Rypniewski W, Zieliński Z, Dowierciał A, Bzowska A, Rode W. Int J Mol Sci 22 4758 (2021)


Reviews citing this publication (1)

  1. Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS). Pozzi C, Lopresti L, Tassone G, Mangani S. Molecules 24 (2019)

Articles citing this publication (19)

  1. Insights into antifolate resistance from malarial DHFR-TS structures. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y. Nat. Struct. Biol. 10 357-365 (2003)
  2. Functional analysis of substrate and cofactor complex structures of a thymidylate synthase-complementing protein. Mathews II, Deacon AM, Canaves JM, McMullan D, Lesley SA, Agarwalla S, Kuhn P. Structure 11 677-690 (2003)
  3. Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors. Phan J, Steadman DJ, Koli S, Ding WC, Minor W, Dunlap RB, Berger SH, Lebioda L. J. Biol. Chem. 276 14170-14177 (2001)
  4. Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP. Almog R, Waddling CA, Maley F, Maley GF, Van Roey P. Protein Sci. 10 988-996 (2001)
  5. Multi-targeted antifolates aimed at avoiding drug resistance form covalent closed inhibitory complexes with human and Escherichia coli thymidylate synthases. Sayre PH, Finer-Moore JS, Fritz TA, Biermann D, Gates SB, MacKellar WC, Patel VF, Stroud RM. J. Mol. Biol. 313 813-829 (2001)
  6. Trapping of an intermediate in the reaction catalyzed by flavin-dependent thymidylate synthase. Mishanina TV, Koehn EM, Conrad JA, Palfey BA, Lesley SA, Kohen A. J. Am. Chem. Soc. 134 4442-4448 (2012)
  7. Folate binding site of flavin-dependent thymidylate synthase. Koehn EM, Perissinotti LL, Moghram S, Prabhakar A, Lesley SA, Mathews II, Kohen A. Proc. Natl. Acad. Sci. U.S.A. 109 15722-15727 (2012)
  8. The crystal structure of thymidylate synthase from Pneumocystis carinii reveals a fungal insert important for drug design. Anderson AC, Perry KM, Freymann DM, Stroud RM. J. Mol. Biol. 297 645-657 (2000)
  9. The only active mutant of thymidylate synthase D169, a residue far from the site of methyl transfer, demonstrates the exquisite nature of enzyme specificity. Birdsall DL, Finer-Moore J, Stroud RM. Protein Eng. 16 229-240 (2003)
  10. Design and characterization of a mutation outside the active site of human thymidylate synthase that affects ligand binding. Cardinale D, Salo-Ahen OM, Guaitoli G, Ferrari S, Venturelli A, Franchini S, Battini R, Ponterini G, Wade RC, Costi MP. Protein Eng. Des. Sel. 23 81-89 (2010)
  11. Explaining an unusually fast parasitic enzyme: folate tail-binding residues dictate substrate positioning and catalysis in Cryptosporidium hominis thymidylate synthase. Martucci WE, Vargo MA, Anderson KS. Biochemistry 47 8902-8911 (2008)
  12. Replacement of Val3 in human thymidylate synthase affects its kinetic properties and intracellular stability . Huang X, Gibson LM, Bell BJ, Lovelace LL, Peña MM, Berger FG, Berger SH, Lebioda L. Biochemistry 49 2475-2482 (2010)
  13. The effect of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c]quinazoline on cell growth, cell cycle, induction of DNA fragmentation, and activity of caspase 3 in murine leukemia L1210 cells and fibroblast NIH-3T3 cells. Jantová S, Letasiová S, Repický A, Ovádeková R, Lakatos B. Cell Biochem Funct 24 519-530 (2006)
  14. Characterization of the bipartite degron that regulates ubiquitin-independent degradation of thymidylate synthase. Barbour KW, Xing YY, Peña EA, Berger FG. Biosci. Rep. 33 165-173 (2013)
  15. Interaction of thymidylate synthase with the 5'-thiophosphates, 5'-dithiophosphates, 5'-H-phosphonates and 5'-S-thiosulfates of 2'-deoxyuridine, thymidine and 5-fluoro-2'-deoxyuridine. Gołos B, Dzik JM, Kazimierczuk Z, Cieśla J, Zieliński Z, Jankowska J, Kraszewski A, Stawiński J, Rode W, Shugar D. Biol. Chem. 382 1439-1445 (2001)
  16. Molecular docking studies on quinazoline antifolate derivatives as human thymidylate synthase inhibitors. Srivastava V, Gupta SP, Siddiqi MI, Mishra BN. Bioinformation 4 357-365 (2010)
  17. Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed. Choi YM, Yeo HK, Park YW, Lee JY. PLoS ONE 11 e0168019 (2016)
  18. Combined metabolomics and network pharmacology to elucidate the mechanisms of Dracorhodin Perchlorate in treating diabetic foot ulcer rats. Deng P, Liang H, Wang S, Hao R, Han J, Sun X, Pan X, Li D, Wu Y, Huang Z, Xue J, Chen Z. Front Pharmacol 13 1038656 (2022)
  19. Examination of the reduced affinity of the thymidylate synthase G52S mutation for FdUMP by ab initio and semi-empirical studies. Sapse AM, Capiaux GM, Bertino JR. Mol. Med. 7 200-204 (2001)


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