A current structural perspective on PXR and CAR in drug metabolism

Abstract

Pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that play major roles in the expression of various drug metabolism enzymes and are known for their ligand promiscuity. As with other nuclear receptors, PXR and CAR are each composed of a ligand-binding domain (LBD) and a DNA-binding domain (DBD) connected by a hinge region. Areas covered: This review focuses on the information obtained over the last 15+ years from X-ray crystallography studies of the structure of PXR and CAR. Areas of focus include the mobility of each structure, based on temperature factors (B factors); multimeric interactions; the binding of coregulators and ligands; and how the crystal structures were obtained. The first use of hydrogen-deuterium exchange coupled with mass spectroscopy (HDX-MS) to study compound-protein interactions in the PXR-LBD is also addressed. Expert opinion: X-ray crystallography studies have provided us with an excellent understanding of how the LBDs of each receptor function; however, many questions remain concerning the structure of these receptors. Future research should focus on determining the co-crystal structure of an antagonist bound to PXR and on studying the structural aspects of the full-length CAR and PXR proteins.

<p>ARQ-197 enhances the antitumor effect of sorafenib in hepatocellular carcinoma cells via decelerating its intracellular clearance</p>

“…Moreover, ARQ-197 also inhibited the activation of PXR, which is the key regulator for exogenous drug metabolism and detoxification in cells. 79,80 Previous studies have also shown that sorafenib can act as a ligand/agonist for PXR during treatment, promoting the expression of PXR downstream drug resistance-related genes by inducing PXR's transcription factor activity, ultimately resulting in sorafenib resistance. 47,81 In HCC cells, the transcription factor ETS-1, an important effector of HGF/c-MET signaling pathway, could function as a co-regulator of PXR and enhance sorafenib resistance.…”

Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer

“…The LBD is characterized by the presence of a hydrophobic pocket that entraps ligands. Unlike the ligand cavity of most NRs, the binding pocket of PXR is prominent for being large and highly flexible, which enables it to accommodate ligands of great diversity in terms of their chemical scaffold, size, lipophilicity, and surface area . Figure shows reported modulators of PXR in a manner that illustrates the large chemical space that they encompass, thus providing an impression of the extensive range of their physiochemical properties.…”

Effect of panaxytriol on cytochrome P450 3A4 via the pregnane X receptor regulatory pathway

“…PXR is crucial in regulating the expression of CYP3A4 enzyme, which mediates the metabolic process of many clinical prescription drugs (Liu, Lim, & Hu, ). Similar to the other nuclear receptors, PXR also includes DNA‐binding domain and ligand‐binding domain (Buchman, Chai, & Chen, ). PXR can be activated by combining with a large number of ligands for various structural and chemical properties (Banerjee, Robbins, & Chen, ), including steroids (Chianese, Sepe, & Limongelli, ), rifampicin (Kodama, Yamazaki, & Negishi, ), bile acid (Wang, Wang, & Lu, ), dexamethasone (Ponce‐Ruiz, Rojas‐García, & Barrón‐Vivanco, ), phenobarbital (Chen, Bao, & Piekos, ), HIV protease inhibitor ritonavir (Liu, Xu, & Hui, ), hyperforin (Taneja, Chu, & Maturu, ), and so forth.…”