Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks

Chembiochem. 2023 Nov 2;24(21):e202300439. doi: 10.1002/cbic.202300439. Epub 2023 Sep 7.

Abstract

Natural products are often uniquely suited to modulate protein-protein interactions (PPIs) due to their architectural and functional group complexity relative to synthetic molecules. Here we demonstrate that the natural product garcinolic acid allosterically blocks the CBP/p300 KIX PPI network and displays excellent selectivity over related GACKIX motifs. It does so via a strong interaction (KD 1 μM) with a non-canonical binding site containing a structurally dynamic loop in CBP/p300 KIX. Garcinolic acid engages full-length CBP in the context of the proteome and in doing so effectively inhibits KIX-dependent transcription in a leukemia model. As the most potent small-molecule KIX inhibitor yet reported, garcinolic acid represents an important step forward in the therapeutic targeting of CBP/p300.

Keywords: CBP/p300; acute myelogenous leukemia; cMyb; natural product; protein-protein interaction inhibitor.

Publication types

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

MeSH terms

  • Binding Sites
  • CREB-Binding Protein* / chemistry
  • Protein Binding
  • Protein Domains
  • Protein Structure, Tertiary

Substances

  • CREB-Binding Protein