2ONB

Human Thymidylate Synthase at low salt conditions with PDPA bound

2ONB の概要

• エントリーDOI: 10.2210/pdb2onb/pdb
• 関連するPDBエントリー: 1YPV
• 分子名称: Thymidylate synthetase, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: diphosphonic acid, fdump, zd9331, heteroinhibition, 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: 36429.59

構造登録者

Lovelace, L.L.,Gibson, L.M.,Lebioda, L. (登録日: 2007-01-23, 公開日: 2007-04-10, 最終更新日: 2024-10-30)

主引用文献

Lovelace, L.L.,Gibson, L.M.,Lebioda, L.
Cooperative Inhibition of Human Thymidylate Synthase by Mixtures of Active Site Binding and Allosteric Inhibitors
Biochemistry, 46:2823-2830, 2007

PubMed Abstract: Thymidylate synthase (TS) is a target in the chemotherapy of colorectal cancer and some other neoplasms. It catalyzes the transfer of a methyl group from methylenetetrahydrofolate to dUMP to form dTMP. On the basis of structural considerations, we have introduced 1,3-propanediphosphonic acid (PDPA) as an allosteric inhibitor of human TS (hTS); it is proposed that PDPA acts by stabilizing an inactive conformer of loop 181-197. Kinetic studies showed that PDPA is a mixed (noncompetitive) inhibitor versus dUMP. In contrast, versus methylenetrahydrofolate at concentrations lower than 0.25 microM, PDPA is an uncompetitive inhibitor, while at PDPA concentrations higher than 1 microM the inhibiton is noncompetive, as expected. At the concentrations corresponding to uncompetitive inhibition, PDPA shows positive cooperativity with an antifolate inhibitor, ZD9331, which binds to the active conformer. PDPA binding leads to the formation of hTS tetramers, but not higher oligomers. These data are consistent with a model in which hTS exists preferably as an asymmetric dimer with one subunit in the active conformation of loop 181-197 and the other in the inactive conformation.

PubMed: 17297914
DOI: 10.1021/bi061309j

実験手法

X-RAY DIFFRACTION (2.7 Å)