1. Academic Validation
  2. Identification of small-molecule antagonists that inhibit an activator: coactivator interaction

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

  • Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17622-7. doi: 10.1073/pnas.0406374101.
Jennifer L Best 1 Carlos A Amezcua Bernhard Mayr Lawrence Flechner Christopher M Murawsky Beverly Emerson Tsaffrir Zor Kevin H Gardner Marc Montminy
Affiliations

Affiliation

  • 1 Department of Peptide Biology and Regulatory Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1002, USA.
Abstract

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.

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