Language
English
Publication Date
12-22-2025
Journal
Journal of Biological Chemistry
DOI
10.1016/j.jbc.2025.111080
PMID
41443415
Abstract
ΔFOSB, a member of the AP-1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, and that they may hinder the ΔFOSB bZIP α-helix from binding to the major groove of DNA. In vivo, direct administration of one such compound, JPC0661, into the brain reduces ΔFOSB occupancy at genomic AP-1 consensus sites by approximately 60% as determined by CUT&RUN-sequencing. These findings suggest that DNA binding and release by AP-1 transcription factors can be controlled via small molecules that dock into a novel site that falls outside of the DNA-binding cleft. Minimal sequence conservation across 29 bZIP domain-containing transcription factors in this druggable groove suggests that it can be exploited to develop AP-1-subunit-selective compounds. Our studies thus reveal a novel strategy to design small-molecule inhibitors of ΔFOSB and other members of the bZIP transcription factor family.
Keywords
AP-1 transcription factor (AP-1), CUT&RUN, DNA-protein interaction, bZIP domain, druggable sites, gene regulation, small molecule inhibitors of transcription factors, structural biology, transcriptional reprogramming, ΔFOSB
Published Open-Access
yes
Recommended Citation
McNeme, Sean; Yim, Yun Young; Kumar, Ashwani; et al., "Discovery of Small Molecules and a Druggable Groove That Regulate DNA Binding and Release of the AP-1 Transcription Factor ΔFOSB" (2025). Faculty, Staff and Students Publications. 5274.
https://digitalcommons.library.tmc.edu/baylor_docs/5274