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

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Alcohol Oxidoreductases; Amino Acid Motifs; Catalytic Domain; Crystallography, X-Ray; DNA-Binding Proteins; Drug Design; Enzyme Inhibitors; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Methionine; Models, Molecular; Nerve Tissue Proteins; Protein Binding


Biochemistry | Biochemistry, Biophysics, and Structural Biology | Medicinal-Pharmaceutical Chemistry | Molecular Biology


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. Elsevier B.V. All rights reserved.

DOI of Published Version



FEBS 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

Journal/Book/Conference Title

FEBS letters


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.

Related Resources

Link to Article in PubMed

PubMed ID