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

Efren Garcia-Maldonado, Andrew D. Huber (), Sergio C. Chai, Stanley Nithianantham, Yongtao Li, Jing Wu, Shyaron Poudel, Darcie J. Miller, Jayaraman Seetharaman and Taosheng Chen ()
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Efren Garcia-Maldonado: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Andrew D. Huber: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Sergio C. Chai: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Stanley Nithianantham: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Yongtao Li: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Jing Wu: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Shyaron Poudel: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Darcie J. Miller: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Jayaraman Seetharaman: St. Jude Children’s Research Hospital, 262 Danny Thomas Place
Taosheng Chen: St. Jude Children’s Research Hospital, 262 Danny Thomas Place

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48472-1

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