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

•CtBP1 & 2 are transcriptional coregulators that have been linked to human cancers.•Crystal structures of CtBP reveal stereochemistry of binding substrate MTOB.•Two features identified, a hydrophilic channel and key Trp, are unique to CtBP.•These results provide a basis for design of specific th...

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Bibliographic Details
Published in:FEBS letters 2014-05, Vol.588 (9), p.1743-1748
Main Authors: Hilbert, Brendan J., Grossman, Steven R., Schiffer, Celia A., Royer, William E.
Format: Article
Language:English
Subjects:
4-Methylthio 2-oxobutyric acid
adenomatous polyposis coli
Alcohol Oxidoreductases - antagonists & inhibitors
Alcohol Oxidoreductases - chemistry
alternative reading frame
Amino Acid Motifs
APC
ARF
C-terminal Binding Protein
Cancer target
Catalytic Domain
Crystallography, X-Ray
CtBP
d-isomer specific 2-hydroxyacid dehydrogenases
d2-HDH
Dehydrogenase
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - chemistry
Drug Design
Enzyme Inhibitors - chemistry
glyoxylate reductase/hydroxypyruvate reductase
GRHPR
HIPK2
homeodomain-interacting protein kinase 2
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Methionine - analogs & derivatives
Methionine - chemistry
Models, Molecular
MTOB
NAD
NADH
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - chemistry
nicotinamide adenine dinucleotide
PHGDH
phosphoglycerate dehydrogenase
Protein Binding
Transcriptional coregulator
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Description
Summary:•CtBP1 & 2 are transcriptional coregulators that have been linked to human cancers.•Crystal structures of CtBP reveal stereochemistry of binding substrate MTOB.•Two features identified, a hydrophilic channel and key Trp, are unique to CtBP.•These results provide a basis for design of specific therapeutic CtBP inhibitors. 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.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2014.03.026