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

FEBS Lett. 2014 May 2;588(9):1743-8. doi: 10.1016/j.febslet.2014.03.026. Epub 2014 Mar 19.

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.

Keywords: Cancer target; Dehydrogenase; NADH; Transcriptional coregulator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / chemistry*
  • Amino Acid Motifs
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / chemistry*
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Methionine / analogs & derivatives*
  • Methionine / chemistry
  • Models, Molecular
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / chemistry*
  • Protein Binding

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Nerve Tissue Proteins
  • 2-keto-4-methylthiobutyric acid
  • Methionine
  • Alcohol Oxidoreductases
  • CTBP2 protein, human
  • C-terminal binding protein

Associated data

  • PDB/4LCE
  • PDB/4LCJ