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Identification of Kinase-substrate Pairs Using High Throughput Screening
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Published on: August 29, 2015

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

Brendan J Hilbert1, Steven R Grossman2, Celia A Schiffer1

  • 1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

FEBS Letters
|March 25, 2014
PubMed

Insights

Oncogenic C-terminal Binding Proteins (CtBP) 1 and 2 were studied using 4-Methylthio 2-oxobutyric acid (MTOB). Crystal structures reveal unique features for developing targeted anti-cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • C-terminal Binding Proteins (CtBP) 1 and 2 are oncogenic corepressors.
  • These proteins contain regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains.
  • 4-Methylthio 2-oxobutyric acid (MTOB) can inhibit CtBP activity.

Purpose of the Study:

  • To elucidate the structural basis of CtBP inhibition by MTOB.
  • To identify unique structural features of CtBP d2-HDH domains.
  • To explore opportunities for developing selective anti-cancer drugs targeting CtBP.

Main Methods:

  • X-ray crystallography was used to determine the structures of human CtBP1 and CtBP2.
  • Complex structures were solved in the presence of MTOB and NAD(+).

Main Results:

  • Crystal structures revealed two key features in CtBP1 and CtBP2: a conserved tryptophan for substrate specificity and a hydrophilic cavity linking MTOB to NAD(+).
  • These identified features are not present in other d2-HDH enzymes.
  • MTOB demonstrated substrate inhibition, interfering with CtBP oncogenic activity.

Conclusions:

  • The unique structural features of CtBP1 and CtBP2 provide a basis for developing highly selective inhibitors.
  • Targeting CtBP with novel inhibitors holds promise for anti-neoplastic therapies.
  • Understanding CtBP-MTOB interactions is crucial for cancer drug development.
Keywords:
Cancer targetDehydrogenaseNADHTranscriptional coregulator

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