5X4X

Mutant human thymidylate synthase A191K crystallized in a sulfate-containing condition

5X4X の概要

• エントリーDOI: 10.2210/pdb5x4x/pdb
• 関連するPDBエントリー: 5X4W 5X4Y 5X5A 5X5D 5X5Q 5X66 5X67 5X69
• 分子名称: Thymidylate synthase, SULFATE ION (3 entities in total)
• 機能のキーワード: methyltransferase, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : P04818
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36100.24

構造登録者

Chen, D.,Jansson, A.,Larsson, A.,Nordlund, P. (登録日: 2017-02-14, 公開日: 2017-06-28, 最終更新日: 2023-11-22)

主引用文献

Chen, D.,Jansson, A.,Sim, D.,Larsson, A.,Nordlund, P.
Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states
J. Biol. Chem., 292:13449-13458, 2017

PubMed Abstract: Thymidylate synthase (TS) is the sole enzyme responsible for biosynthesis of thymidylate (TMP) and is essential for cell proliferation and survival. Inhibition of human TS (hTS) has been extensively investigated for cancer chemotherapy, but several aspects of its activity and regulation are still uncertain. In this study, we performed comprehensive structural and biophysical studies of hTS using crystallography and thermal shift assay and provided the first detailed structural information on the conformational changes induced by ligand binding to the hTS active site. We found that upon binding of the antifolate agents raltitrexed and nolatrexed, the two insert regions in hTS, the functions of which are unclear, undergo positional shifts toward the catalytic center. We investigated the inactive conformation of hTS and found that the two insert regions are also involved in the conformational transition between the active and inactive state of hTS. Moreover, we identified a ligand-binding site in the dimer interface, suggesting that the cavity in the dimer interface could serve as an allosteric site of hTS to regulate the conformational switching between the active and inactive states. On the basis of these findings, we propose a regulatory mechanism of hTS activity that involves allosteric regulation of interactions of hTS with its own mRNA depending on cellular demands for TMP.

PubMed: 28634233
DOI: 10.1074/jbc.M117.787267

実験手法

X-RAY DIFFRACTION (2.31 Å)