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

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, negative...

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Vydané v:	Nature communications Ročník 15; číslo 1; s. 4054 - 14
Hlavní autori:	Garcia-Maldonado, Efren, Huber, Andrew D., Chai, Sergio C., Nithianantham, Stanley, Li, Yongtao, Wu, Jing, Poudel, Shyaron, Miller, Darcie J., Seetharaman, Jayaraman, Chen, Taosheng
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 14.05.2024 Nature Publishing Group Nature Portfolio
Predmet:	13/1 38/109 38/70 38/77 38/88 631/45/612/388 631/535/1266 631/92/609 82/83 Agonists Antagonists Crystallography, X-Ray Detoxification Drug development Drug efficacy Drug metabolism Drugs Hep G2 Cells Humanities and Social Sciences Humans INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Ligands mechanism of action Models, Molecular Molecular modelling multidisciplinary Nuclear receptors Nuclear safety Pregnane X Receptor - antagonists & inhibitors Pregnane X Receptor - metabolism Protein Binding Receptors Science Science (multidisciplinary) Therapeutic targets Transcription factors x-ray crystallography
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. PXR is a receptor activated by diverse compounds that triggers detoxification pathways in the cell, and blocking this receptor may increase the effectiveness of certain drugs. Here, the authors present the structural basis of PXR inhibition.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 AC02-06CH11357; SC0012704 USDOE Office of Science (SC), Basic Energy Sciences (BES) USDOE Office of Science (SC), Biological and Environmental Research (BER)
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-48472-1