1TLC

THYMIDYLATE SYNTHASE COMPLEXED WITH DGMP AND FOLATE ANALOG 1843U89

1TLC の概要

• エントリーDOI: 10.2210/pdb1tlc/pdb
• 分子名称: THYMIDYLATE SYNTHASE, 2'-DEOXYGUANOSINE-5'-MONOPHOSPHATE, S)-2-(5(((1,2-DIHYDRO-3-METHYL-1-OXOBENZO(F)QUINAZOLIN-9-YL)METHYL)AMINO)1-OXO-2-ISOINDOLINYL)GLUTARIC ACID, ... (4 entities in total)
• 機能のキーワード: methyltransferase
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62782.77

構造登録者

Weichsel, A.,Montfort, W.R.,Ciesla, J.,Maley, F. (登録日: 1995-03-07, 公開日: 1995-06-03, 最終更新日: 2025-03-26)

主引用文献

Weichsel, A.,Montfort, W.R.,Ciesla, J.,Maley, F.
Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.
Proc.Natl.Acad.Sci.USA, 92:3493-3497, 1995

PubMed Abstract: A folate analogue, 1843U89 (U89), with potential as a chemotherapeutic agent due to its potent and specific inhibition of thymidylate synthase (TS; EC 2.1.1.45), greatly enhances not only the binding of 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and dUMP to Escherichia coli TS but also that of dGMP, GMP, dIMP, and IMP. Guanine nucleotide binding was first detected by CD analysis, which revealed a unique spectrum for the TS-dGMP-U89 ternary complex. The quantitative binding of dGMP relative to GMP, FdUMP, and dUMP was determined in the presence and absence of U89 by ultrafiltration analysis, which revealed that although the binding of GMP and dGMP could not be detected in the absence of U89 both were bound in its presence. The Kd for dGMP was about the same as that for dUMP and FdUMP, with binding of the latter two nucleotides being increased by two orders of magnitude by U89. An explanation for the binding of dGMP was provided by x-ray diffraction studies that revealed an extensive stacking interaction between the guanine of dGMP and the benzoquinazoline ring of U89 and hydrogen bonds similar to those involved in dUMP binding. In addition, binding energy was provided through a water molecule that formed hydrogen bonds to both N7 of dGMP and the hydroxyl of Tyr-94. Accommodation of the larger dGMP molecule was accomplished through a distortion of the active site and a shift of the deoxyribose moiety to a new position. These rearrangements also enabled the binding of GMP to occur by creating a pocket for the ribose 2' hydroxyl group, overcoming the normal TS discrimination against nucleotides containing the 2' hydroxyl.

PubMed: 7724588
DOI: 10.1073/pnas.92.8.3493

実験手法

X-RAY DIFFRACTION (2.1 Å)