7YFK

The structure of human pregnane X receptor in complex with an SRC-1 coactivator peptide and a limonoid compound, nomilin

Replaces:  7CHG

Summary for 7YFK

• Entry DOI: 10.2210/pdb7yfk/pdb
• Descriptor: Nuclear receptor subfamily 1 group I member 2,Nuclear receptor coactivator 1, Nomilin (3 entities in total)
• Functional Keywords: complex, activator, transcription, drug binding, nuclear receptor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 78143.82

Authors

Xia, Y.,Yao, D.,Huang, C.,Cao, Y. (deposition date: 2022-07-08, release date: 2023-06-14, Last modification date: 2023-11-29)

Primary citation

Fan, S.,Yan, Y.,Xia, Y.,Zhou, Z.,Luo, L.,Zhu, M.,Han, Y.,Yao, D.,Zhang, L.,Fang, M.,Peng, L.,Yu, J.,Liu, Y.,Gao, X.,Guan, H.,Li, H.,Wang, C.,Wu, X.,Zhu, H.,Cao, Y.,Huang, C.
Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions.
Nat Commun, 14:3368-3368, 2023

PubMed Abstract: Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.

PubMed: 37291126
DOI: 10.1038/s41467-023-39118-9

Experimental method

X-RAY DIFFRACTION (2.1 Å)