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Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design
Author(s) -
Hilbert Brendan J.,
Grossman Steven R.,
Schiffer Celia A.,
Royer William E.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.03.026
Subject(s) - nad+ kinase , active site , chemistry , enzyme , substrate (aquarium) , biochemistry , dehydrogenase , binding site , hydrolase , stereochemistry , microbiology and biotechnology , biology , ecology
The oncogenic corepressors C‐terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d ‐isomer specific 2‐hydroxyacid dehydrogenase ( d 2‐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 d 2‐HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti‐neoplastic CtBP inhibitors.