Discovery of small molecules and a druggable groove that regulate DNA binding and release of the AP-1 transcription factor ΔFOSB
文献类型：期刊论文
| 作者 | Mcneme, Sean3,4; Yim, Yun Young2,18; Kumar, Ashwani3,4,10; Li, Yi3,4,11; Hughes, Brandon2,18; St Romain, Corey Peyton17; Aglyamova, Galina3,4,7; Chen, Jianping3,4,6; Nguyen, Nghi D.16; Fan, Shanghua3,4 |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2026-02-01 |
| 卷号 | 302期号:2页码:23 |
| ISSN号 | 0021-9258 |
| DOI | 10.1016/j.jbc.2025.111080 |
| 通讯作者 | Rudenko, Gabby(garudenk@utmb.edu) |
| 英文摘要 | OFOSB, a member of the activator protein 1 (AP-1) family of transcription factors (TFs), mediates long-term neuroadaptations underlying drug addiction, seizure-related cognitive decline, dyskinesias, and several other chronic conditions. AP-1 TFs are notoriously difficult to modulate pharmacologically because of the absence of well-defined binding pockets. Here, we identify a novel site on OFOSB, located outside the DNA-binding cleft, which 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 OFOSB basic leucine zipper (bZIP) a-helix from binding to the major groove of DNA. In vivo, direct administration of one such compound, JPC0661, into the brain reduces OFOSB 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 TFs can be controlled via small molecules that dock into a novel site that falls outside the DNA-binding cleft. Minimal sequence conservation across 29 bZIP domain-containing TFs 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 OFOSB and other members of the bZIP TF family. |
| WOS关键词 | EXPRESSION ; INHIBITOR ; GENE ; JUN ; STABILITY ; MECHANISM ; CONTINUUM ; PROTEINS ; DYNAMICS ; SEIZURE |
| 资助项目 | National Institutes of Health, National Institute on Drug Abuse[R01DA040621] ; National Institutes of Health, National Institute on Drug Abuse[R01DA040621-03S1] ; National Institutes of Health, National Institute on Drug Abuse[R01DA040621-07S1] ; John D. Stobo, M.D. Distinguished Chair Endowment Fund ; Edith & Robert Zinn Chair in Drug Discovery Endowment Fund ; Jeane B. Kempner Award (University of Texas Medical Branch) ; Stuart & Suzanne Steele Massachusetts General Hospital Research Scholar Award ; Precision Therapeutics Unit in the Center for Genomic Medicine at Massachusetts General Hospital ; Cancer Prevention and Research Institute of Texas, Combinatorial Drug Discovery Program[RP150578] ; National Institutes of Health, National Institute of Neurological Disorders and Stroke[R01NS085171] ; National Institutes of Health, National Institute on Aging[F30AG085919] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001683370900001 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322833]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Rudenko, Gabby |
| 作者单位 | 1.Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY USA 2.Icahn Sch Med Mt Sinai, Nash Family Dept Neurosci, New York, NY USA 3.Univ Texas Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA 4.Univ Texas Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77555 USA 5.Univ Hawaii Manoa, Honolulu, HI USA 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 7.Univ Houston, Dept Biol, Houston, TX USA 8.K2B Therapeut, Cambridge, MA USA 9.Tufts Univ, Dept Chem & Biol Engn, Medford, MA USA 10.Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH USA |
| 推荐引用方式 GB/T 7714 | 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[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2026,302(2):23. |
| APA | Mcneme, Sean.,Yim, Yun Young.,Kumar, Ashwani.,Li, Yi.,Hughes, Brandon.,...&Rudenko, Gabby.(2026).Discovery of small molecules and a druggable groove that regulate DNA binding and release of the AP-1 transcription factor ΔFOSB.JOURNAL OF BIOLOGICAL CHEMISTRY,302(2),23. |
| MLA | Mcneme, Sean,et al."Discovery of small molecules and a druggable groove that regulate DNA binding and release of the AP-1 transcription factor ΔFOSB".JOURNAL OF BIOLOGICAL CHEMISTRY 302.2(2026):23. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。