Identification of small-molecule antagonist that inhibit an activator:coactivator interaction

Jennifer L. Best, Carlos A. Amezcua, Bernhard Mayr, Lawrence Flechner, Christopher M. Murawsky, Beverly Emerson, Tsaffrir Zor, Kevin H. Gardner, Marc Montminy

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Phosphorylation of the cAMP response element binding protein (CREB) at Ser-133 in response to hormonal stimuli triggers cellular gene expression via the recruitment of the histone acetylase coactivator paralogs CREB binding protein (CBP) and p300 to the promoter. The NMR structure of the CREB:CBP complex, using relevant interaction domains called KID and KIX, respectively, reveals a shallow hydrophobic groove on the surface of KIX that accommodates an amphipathic helix in phospho (Ser-133) KID. Using an NMR-based screening approach on a preselected small-molecule library, we identified several compounds that bind to different surfaces on KIX. One of these, KG-501 (2-naphthol-AS-E-phosphate), targeted a surface distal to the CREB binding groove that includes Arg-600, a residue that is required for the CREB:CBP interaction. When added to live cells, KG-501 disrupted the CREB: CBP complex and attenuated target gene induction in response to cAMP agonist. These results demonstrate the ability of small molecules to interfere with second-messenger signaling cascades by inhibiting specific protein-protein interactions in the nucleus.

Original languageEnglish (US)
Pages (from-to)17622-17627
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 21 2004


  • Transcription
  • cAMP response element binding protein

ASJC Scopus subject areas

  • General


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