Trends in Pharmacological Sciences
Research updateThe PXR crystal structure: the end of the beginning
Section snippets
The crystal structure of the PXR ligand binding domain
The desire to decrease the time-line in clinical drug discovery has led to the evolution of several fast-throughput screening assays to detect binding of ligands to PXR 1, 9.
To streamline the process of identification of PXR ligands even further, Watkins et al. recently solved the crystal structure of the PXR ligand binding domain (LBD) revealing a highly flexible LBD that is largely hydrophobic with five polar residues capable of both donating and accepting hydrogen bonds [10]. The ligand
Molecular modeling
Without the PXR LBD crystal structure it was theoretically possible to predict the structure of potential PXR ligands computationally and to model the important structural features of these ligands that allowed them to interact with PXR [15], based on published EC50 values for activation and deactivation of human PXR. However, what we cannot understand from a potential PXR ligand structure alone is the exact orientation of the bound ligand in the PXR pocket without docking the molecule in the
Natural allelic variants of PXR
Because the PXR LBD is so divergent among species [9], it has been hypothesized that sequence variations in PXR might contribute to variability in human CYP3A4 induction [18]. Surprisingly, natural PXR allelic variants, particularly those in the LBD, were rare 18, 19. Indeed, the allelic frequencies of one of the three PXR ligand binding variants was not more than 1.6% in African Americans and 0.2% in Caucasians (i.e. only one Caucasian person in 500 would be heterozygous for this variant).
Future perspectives and conclusions
This structural information can now be used to efficiently screen drugs in the development pipeline for binding to PXR. Moreover, information from modeling drug candidates for their potential to bind the PXR LBD will foster more rapid decision making with regard to the potential for any molecule to cause drug interactions and for further structure optimization.
However, because questions remain regarding the accurate prediction of the many factors that drive ligand binding to PXR, a strictly
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Discrepancy in interactions and conformational dynamics of pregnane X receptor (PXR) bound to an agonist and a novel competitive antagonist
2022, Computational and Structural Biotechnology JournalCitation Excerpt :Moreover, while many NRs exhibit a three-stranded β-sheet in their LBD, PXR comes with two additional strands. These extra β-sheets, together with the additional α2′, contribute to a larger and more flexible LBD, when compared to other NR-LBDs [19–21]. This increased flexibility allows accommodation of diverse set of ligands to the ligand binding pocket (LBP) (Fig. 1B), which is a unique characteristic of PXR.
Developing adnectins that target src co-activator binding to PXR: A structural approach toward understanding promiscuity of PXR
2015, Journal of Molecular BiologyCitation Excerpt :The two most important target genes of PXR activation are cytochrome P450 (CYP; CYP3A4) and multidrug resistance gene 1 [9–11]. Together, these two genes are responsible for elimination of more than 50% of all drugs [4,12,13]. The increase in expression of drug metabolizing genes mediated by PXR can reduce the clinical efficacy of the drug and can cause dangerous drug–drug interactions by enhancing metabolism of other drugs.
Neurosteroid regulation of central nervous system development
2007, Pharmacology and TherapeuticsConformational adaptation of nuclear receptor ligand binding domains to agonists: Potential for novel approaches to ligand design
2005, Journal of Steroid Biochemistry and Molecular BiologyEndocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor
2003, Toxicology and Applied Pharmacology
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