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

2014/03/19 by Brendan J. Hilbert, Steven R. Grossman, Celia A. Schiffer +1 · 24 citations
Biochemistry, Genetics and Molecular Biology · #Kruppel-like factors research #Cancer-related gene regulation #Genetic Syndromes and Imprinting

paper · pdf · doi:10.1016/j.febslet.2014.03.026

Abstract

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.

Citations

• Phasercrystallographic software

Cited by

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• CtBP- an emerging oncogene and novel small molecule drug target: Advances in the understanding of its oncogenic action and identification of therapeutic inhibitors. [europepmc]
• The Role of CtBP1 in Oncogenic Processes and Its Potential as a Therapeutic Target. [europepmc]
• Molecular link between glucose and glutamine consumption in cancer cells mediated by CtBP and SIRT4. [europepmc]
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• Classification, substrate specificity and structural features of D-2-hydroxyacid dehydrogenases: 2HADH knowledgebase. [europepmc]
• Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities. [europepmc]
• Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein. [europepmc]
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• C-Terminal Binding Proteins Promote Neurogenesis and Oligodendrogenesis in the Subventricular Zone. [europepmc]
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• Oncogene EVI1 Drives Acute Myeloid Leukemia Via a Targetable Interaction with CTBP2 [europepmc]

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