Discovery of a druggable site regulating DNA Binding of the AP1 transcription factor, deltaFOSb

ΔFOSB, a member of the AP1 family of transcription factors, mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP1 transcription factors are notoriously difficult to modulate pharmacologically due to the absence of well-defined binding pockets. Here, we identify a novel allosteric site on ΔFOSB, located outside the DNA-binding cleft, that accommodates small molecules and regulates DNA binding and release. We show that sulfonic acid-containing compounds bind to this site via an induced-fit mechanism, reorienting side chains critical for DNA binding, thereby likely hindering the ΔFOSB bZIP α-helix from binding in the major groove of DNA. In vivo, direct administration of lead compound JPC0661 into the brain reduces ΔFOSB occupancy at genomic AP1 consensus sites by approximately 60% as determined by CUT&RUN-sequencing. These findings demonstrate that DNA binding and release by AP1 transcription factors can be controlled via small molecules docking into a novel allosteric binding site.