8r00
Crystal structure of the human PXR ligand-binding domain in complex with furanodienone
Structural highlights
FunctionNR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases. An abundant ginger compound furanodienone alleviates gut inflammation via the xenobiotic nuclear receptor PXR in mice.,Wang X, Zhang G, Bian Z, Chow V, Grimaldi M, Carivenc C, Sirounian S, Li H, Sladekova L, Motta S, Luperi Y, Gong Y, Costello C, Li L, Jachimowicz M, Guo M, Hu S, Wilson D, Balaguer P, Bourguet W, Mani S, Bonati L, Peng H, March J, Wang H, Wang S, Krause HM, Liu J Nat Commun. 2025 Feb 3;16(1):1280. doi: 10.1038/s41467-025-56624-0. PMID:39900639[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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