Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks

• Published in: Chembiochem : a European journal of chemical biology Vol. 24; no. 21; p. e202300439
• Main Authors: Breen, Meghan E, Joy, Stephen T, Baruti, Omari J, Beyersdorf, Matthew S, Henley, Madeleine J, De Salle, Samantha N, Ycas, Peter D, Croskey, Ayza, Cierpicki, Tomasz, Pomerantz, William C K, Mapp, Anna K
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 02.11.2023
• Subjects: Binding Sites; CREB-Binding Protein - chemistry; Functional groups; Leukemia; Natural products; Protein Binding; Protein Domains; Protein interaction; Protein Structure, Tertiary; Proteins; Proteomes; Therapeutic targets; acute myelogenous leukemia; protein-protein interaction inhibitor; cMyb; CBP/p300; natural product
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202300439

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 (K 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.