Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
Amino Acid Motifs
Hydrophobic and Hydrophilic Interactions
Nerve Tissue Proteins
Biochemistry, Biophysics, and Structural Biology
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AbstractThe 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. Elsevier B.V. All rights reserved.
SourceFEBS Lett. 2014 May 2;588(9):1743-8. doi: 10.1016/j.febslet.2014.03.026. Epub 2014 Mar 19. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/26068
First author Brendan Hilbert is a doctoral student in the Biochemistry and Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
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