1HW3

STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS

1HW3 の概要

• エントリーDOI: 10.2210/pdb1hw3/pdb
• 関連するPDBエントリー: 1HW4
• 分子名称: THYMIDYLATE SYNTHASE, SULFATE ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: thymidylate synthase, methyltransferase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36513.72

構造登録者

Phan, J.,Steadman, J.D.,Koli, S.,Ding, W.C.,Minor, W.,Dunlap, R.B.,Berger, S.H.,Lebioda, L. (登録日: 2001-01-09, 公開日: 2001-01-24, 最終更新日: 2024-10-30)

主引用文献

Phan, J.,Steadman, D.J.,Koli, S.,Ding, W.C.,Minor, W.,Dunlap, R.B.,Berger, S.H.,Lebioda, L.
Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors.
J.Biol.Chem., 276:14170-14177, 2001

PubMed Abstract: Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms. The emergence of resistance to the treatment is often related to the increased levels of TS in cancer cells, which have been linked to the elimination of TS binding to its own mRNA upon drug binding, a feedback regulatory mechanism, and/or to the increased stability to intracellular degradation of TS.drug complexes (versus unliganded TS). The active site loop of human TS (hTS) has a unique conformation resulted from a rotation by 180 degrees relative to its orientation in bacterial TSs. In this conformation, the enzyme must be inactive, because the catalytic cysteine is no longer positioned in the ligand-binding pocket. The ordered solvent structure obtained from high resolution crystallographic data (2.0 A) suggests that the inactive loop conformation promotes mRNA binding and intracellular degradation of the enzyme. This hypothesis is supported by fluorescence studies, which indicate that in solution both active and inactive forms of hTS are present. The binding of phosphate ion shifts the equilibrium toward the inactive conformation; subsequent dUMP binding reverses the equilibrium toward the active form. Thus, TS inhibition via stabilization of the inactive conformation should lead to less resistance than is observed with presently used drugs, which are analogs of its substrates, dUMP and CH(2)H(4)folate, and bind in the active site, promoting the active conformation. The presence of an extension at the N terminus of native hTS has no significant effect on kinetic properties or crystal structure.

PubMed: 11278511

実験手法

X-RAY DIFFRACTION (2 Å)