Unknown

Dataset Information

0

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design.


ABSTRACT: The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD(+) phosphate. Neither feature is present in other d2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors.

SUBMITTER: Hilbert BJ 

PROVIDER: S-EPMC4072453 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design.

Hilbert Brendan J BJ   Grossman Steven R SR   Schiffer Celia A CA   Royer William E WE  

FEBS letters 20140319 9


The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that lin  ...[more]

Similar Datasets

| S-EPMC3427221 | biostudies-literature
| S-EPMC8602277 | biostudies-literature
| S-EPMC354404 | biostudies-literature
| S-EPMC5693720 | biostudies-literature
| S-EPMC2242479 | biostudies-literature
| S-EPMC2906318 | biostudies-literature
| S-EPMC3503178 | biostudies-literature
| S-EPMC3814792 | biostudies-literature
| S-EPMC4002068 | biostudies-literature
| S-EPMC3630204 | biostudies-literature