9OC3

Transcription factor DeltaFOSB/JUND bZIP domain in complex with an effector molecule

This is a non-PDB format compatible entry.

Summary for 9OC3

• Entry DOI: 10.2210/pdb9oc3/pdb
• Descriptor: Protein FosB, Transcription factor jun-D, (5M)-5-(3-amino-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)-2-phenoxybenzene-1-sulfonic acid, ... (5 entities in total)
• Functional Keywords: deltafosb, ap1 transcription factor, bzip domain, allosteric site, cut&run, in vivo compound administration, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 16899.78

Authors

Machius, M.,Kumar, A.,Rudenko, G. (deposition date: 2025-04-23, release date: 2026-01-07, Last modification date: 2026-02-04)

Primary citation

McNeme, S.,Yim, Y.Y.,Kumar, A.,Li, Y.,Hughes, B.,St Romain, C.P.,Aglyamova, G.,Chen, J.,Nguyen, N.D.,Fan, S.,Stephens, G.S.,Zhao, W.N.,Kruzshak, S.,Estill, M.,Brener, C.,Tofani, S.,Kumar, A.,Chen, E.P.,Takatka, N.,Robison, A.J.,Chen, H.,Powell, R.T.,Haggarty, S.J.,Stephan, C.,Nestler, E.J.,Chin, J.,Machius, M.,Zhou, J.,Rudenko, G.
Discovery of small molecules and a druggable groove that regulate DNA binding and release of the AP-1 transcription factor Delta FOSB.
J.Biol.Chem., 302:111080-111080, 2025

PubMed 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.

PubMed: 41443415
DOI: 10.1016/j.jbc.2025.111080

Experimental method

X-RAY DIFFRACTION (1.73 Å)