8F5Y
Crystal structure of pregnane X receptor ligand binding domain complexed with JQ1
Summary for 8F5Y
| Entry DOI | 10.2210/pdb8f5y/pdb |
| Descriptor | Nuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1, (6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium, ... (4 entities in total) |
| Functional Keywords | nuclear receptor, transcription factor, metabolism, antibiotic, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 78945.80 |
| Authors | Huber, A.D.,Poudel, S.,Seetharaman, J.,Miller, D.J.,Chen, T. (deposition date: 2022-11-15, release date: 2024-02-21, Last modification date: 2024-03-06) |
| Primary citation | Huber, A.D.,Poudel, S.,Wu, J.,Miller, D.J.,Lin, W.,Yang, L.,Bwayi, M.N.,Rimmer, M.A.,Gee, R.R.F.,Seetharaman, J.,Chai, S.C.,Chen, T. A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR. Nucleic Acids Res., 52:1661-1676, 2024 Cited by PubMed Abstract: Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (-)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1's tert-butyl moiety as a PXR anchor and explains binding by (-)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (-)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes. PubMed: 38084912DOI: 10.1093/nar/gkad1175 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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