Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design
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UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyDocument Type
Journal ArticlePublication Date
2014-05-02Keywords
Alcohol OxidoreductasesAmino 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
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Show full item recordAbstract
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.Source
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 siteDOI
10.1016/j.febslet.2014.03.026Permanent Link to this Item
http://hdl.handle.net/20.500.14038/26068PubMed ID
24657618Notes
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 PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.febslet.2014.03.026