Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR

Garcia-Maldonado, Efren; Huber, Andrew D.; Chai, Sergio C.; Nithianantham, Stanley; Li, Yongtao; Wu, Jing; Poudel, Shyaron; Miller, Darcie J.; Seetharaman, Jayaraman; Chen, Taosheng

doi:10.1038/s41467-024-48472-1

Title: Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR

Journal Article · 13 May 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-48472-1 · OSTI ID:2470258

Garcia-Maldonado, Efren ^[1];

^[1];

^[1]; Wu, Jing ^[1]; Poudel, Shyaron ^[1]; Miller, Darcie J. ^[1]; Seetharaman, Jayaraman ^[1];

^[1]

St. Jude Children's Research Hospital, Memphis, TN (United States)

Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 2470258

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
mechanism of action
nuclear receptors
x-ray crystallography

Title: Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR

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