Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states.

ABSTRACT: Thymidylate synthase (TS) is the sole enzyme responsible for de novo 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 invest

SUBMITTER: Chen D 

PROVIDER: S-EPMC5555203 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature