Garcinolic Acid Distinguishes Between GACKIX Domains and Modulates Interaction Networks.

Autor: Breen ME; Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Joy ST; Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Baruti OJ; Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Beyersdorf MS; Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Henley MJ; Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., De Salle SN; Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Ycas PD; Department of Chemistry, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN-55455, USA., Croskey A; Program in Chemical Biology, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Cierpicki T; Department of Pathology, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA., Pomerantz WCK; Department of Chemistry, University of Minnesota, 207 Pleasant St SE, Minneapolis, MN-55455, USA., Mapp AK; Department of Chemistry and Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI-48109, USA.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2023 Nov 02; Vol. 24 (21), pp. e202300439. Date of Electronic Publication: 2023 Sep 07.
DOI: 10.1002/cbic.202300439
Abstrakt: 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 D 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.
(© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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