The Nuclear Xenobiotic Receptor Pregnane X Receptor: Recent Insights and New Challenges

Jillian Orans, Denise G. Teotico and Matthew R. Redinbo

Department of Chemistry (J.O., D.G.T., M.R.R.) and Department of Biochemistry and Biophysics, Program in Molecular Biology and Biotechnology, and the Lineberger Comprehensive Cancer Center (M.R.R.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290

Address all correspondence and requests for reprints to: Matthew R. Redinbo, Ph.D., Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290. E-mail: redinbo{at}unc.edu.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 
The nuclear receptor pregnane X receptor (PXR) plays a key but structurally enigmatic role in human biology. This ligand-regulated transcription factor responds to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs, and regulates the expression of a critical set of protective gene products involved in xenobiotic and endobiotic metabolism. The structural basis of this receptor’s remarkable and unique promiscuity is just now coming into focus. We examine the importance of mobile regions novel to the nuclear receptor ligand-binding domain fold in the ability of PXR to respond to a variety of small and large agonists. We also review the functional roles played by PXR in numerous biological pathways and outline emerging areas for the future examination of this key nuclear xenobiotic receptor.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 
THE NUCLEAR PREGNANE X receptor [PXR; NR1I2, also known as SXR and PAR (1, 2, 3)] is a member of the nuclear receptor (NR) family of ligand-dependent transcriptional factors and a key regulator of genes involved in xenobiotic and endobiotic metabolism. PXR was assigned the role of detecting endogenous pregnanes by Kliewer et al. (4), but has subsequently been adopted as a central xenobiotic receptor that responds to many clinical drugs. PXR functions as a heterodimer with retinoic X receptor-{alpha} (RXR{alpha}) and binds to a variety of response elements (direct repeats DR-3, DR-4, and DR-5, and everted repeats ER-6 and ER-8) in the promoter regions of target genes. Its moderate basal activity and up-regulation of transcriptional events are mediated by recruitment of coactivators of the p160 family [e.g. steroid receptor coactivator (SRC), glucocorticoid receptor interacting protein]; similarly, its repression of gene expression involves physical contacts with transcriptional corepressors. We review recent advances in our understanding of PXR function and structure and present some key challenges for future studies of this nuclear xenobiotic receptor.


    PXR FUNCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 
PXR in Xenobiotic and Endobiotic Detection
The cytochromes P450 (CYP450s) are heme-containing monooxygenases involved in endobiotic and xenobiotic clearance, including the elimination of therapeutic drugs (5). PXR is expressed predominantly in the liver and is activated by a variety of structurally distinct ligands that are known to induce the expression of CYP450 genes central to drug metabolism. These compounds include phenobarbital, rifampicin, dexamethasone, nifedipine, taxol, and hyperforin, the active agent of the herbal remedy St. John’s wort (3, 4, 6). Phase I drug metabolism genes regulated by PXR include several CYP450s (e.g. CYP3A4, CYP2B6, CYP2C8, CYP2C9, and CYP2C19), carboxylesterases, and dehydrogenases, as well as enzymes involved in heme production and the P450 reaction cycle (4, 6, 7, 8, 9, 10, 11, 12, 13). Indeed, PXR has been termed the master regulator of the expression of CYP3A4, which metabolizes more than 50% of human drugs. PXR also controls the expression of the phase II drug metabolism genes encoding UDP-glucoronosyltransferases and glutathione-S-transferases (14, 15, 16, 17, 18), and phase III drug efflux pumps such as multidrug resistance 1 and multidrug resistance protein 2 (7, 19, 20, 21). Thus, PXR is an important and efficient regulator of the expression of genes involved in all phases of drug metabolism and excretion.

PXR is also activated by a variety of endogenous ligands, including pregnanes, bile acids, hormones, and dietary vitamins (1, 4). In response to bile acids and oxysterols, PXR regulates the expression of genes involved in bile acid metabolism and transport, including CYP7A, Oatp2, and 3-hydroxy-3-methylglutaryl coenzyme A synthases (22, 23, 24). These data, and subsequent studies in animal models of cholestatic liver disease, have established that PXR plays a critical role in cholesterol homeostasis and in protecting tissues from potentially toxic endobiotics (25, 26).

Species-Specific Activation
Like most members of the NR superfamily, PXR contains a DNA-binding domain (DBD) connected by a presumably flexible hinge region to a ligand-binding domain (LBD), which contains the ligand-dependent activation function (AF-2) region. Unlike most NRs, however, the LBDs of PXRs from different species exhibit significant sequence divergence. For example, mammalian isoforms of PXR share less than 80% sequence identity within their LBDs compared with more than 90% within their DBDs. Although each of these PXRs is promiscuous in terms of ligand binding (responding to compounds of varying size, shape, and chemical composition), each is also relatively specific to certain regions of chemical space. This feature of PXR activation has been termed "directed promiscuity" (27).

Kocarek et al. (28, 29) first noted striking interspecies differences in cytochrome P450 gene expression in response to known CYP3A inducers, such as the antiglucocorticoid pregnenolone 16-{alpha}-carbonitrile (PCN) and the macrolide antibiotic rifampicin. In-cell, trans-species gene transfer studies later determined that the differential CYP3A gene expression found in rats, rabbits, and humans was not derived from differences in CYP3A sequence, but rather from some other factor (30, 31). After the initial cloning and characterization of mouse and human PXR, it was found that both forms of the receptor were not only activated by many of the compounds known to regulate CYP3A gene expression, but also that they could also bind to response elements in the promoter regions of several CYP3A genes. The mouse form of PXR was strongly activated by both PCN and dexamethasone (4), whereas human PXR was efficiently activated by dexamethasone, rifampicin, and RU486, another antiglucocorticoid (3, 6).

Subsequent transient-transfection experiments established that the regulation of these genes was dependent upon the activation of PXR, and that the activation profiles of the various forms of PXR were remarkably different (31). For example, rabbit PXR could be activated by rifampicin to induce CYP3A gene expression whereas rat PXR could not. Additionally, equal concentrations of PCN could effectively activate rat PXR, but not the rabbit form (31). Jones et al. (32) expanded these profiles to include human and mouse PXR through the use of a novel binding assay. Rifampicin and SR12813, a cholesterol-lowering drug, were found to effectively activate human and rabbit PXR but not rat and mouse forms. PCN was found to potently activate mouse as well as rat PXR but had little effect on the human and rabbit forms. These data correlated well with the patterns of CYP3A gene expression in the liver and intestinal tissues of the various species, proving that the receptor has clearly diverged functionally through the process of evolution. Indeed, several studies have identified individual residues in the LBD that confer species-specific transcriptional activation to the PXRs (27, 33, 34).

Cross-Talk with Other NRs
PXR overlaps functionally with CAR (constitutive androstane receptor) in terms of ligand binding and gene activation. It was noted in 1990 that the treatment of rat hepatocytes with phenobarbital caused distinct expression patterns for the cytochrome P450 isoforms CYP2B and CYP3A (29). It was subsequently shown that both PXR and CAR could both be activated by phenobarbital, and that the effects of phenobarbital on CYP gene expression were mediated by several different NRs (6). PXR became established as a central regulator of CYP3A genes (1, 3, 4), whereas CAR was found to respond to phenobarbital response elements located on CYP2B genes (35, 36, 37). In 2000, Moore et al. (38) showed that both receptors could be activated by some of the same xenobiotic and endobiotic compounds, including rifampicin and phenobarbital. It was then demonstrated that CAR and PXR cross-talk extended to DNA binding, with the finding that PXR could up-regulate CYP2B gene products using the same response element employed by CAR, and vice versa, for CAR’s up-regulation of CYP3A gene products (8). Thus, PXR and CAR work in concert by binding to the same ligands and DNA response elements to control target gene expression. Recent studies have established that PXR, CAR, and FOXO1, a forkhead transcription factor, function together to regulate the expression of a variety of target genes central to drug metabolism and gluconeogenesis (39).

Subcellular Localization
Studies to determine the subcellular localization of PXR have provided conflicting results. Two groups have reported that human PXR is consistently localized in the nucleus, regardless of the addition of ligand. In one such study, Kawana et al. (40) used transient expression in HeLa cells to show that PXR was localized in the nucleus in the absence of ligand. They also identified a nuclear localization signal in the DBD of PXR. Removal of the DBD resulted in solely cytoplasmic localization, and mutation of the putative nuclear localization signal resulted in PXR localization in both the cytoplasm and the nucleus. These results are consistent with immunostaining assays that found human PXR to be exclusively located in the nucleus both with and without ligand (41). Other studies, however, have provided evidence to the contrary. PXR from mouse liver was found to be localized in the cytoplasm and translocated to the nucleus only upon addition of PCN or other agonists (40, 42). The discrepancies in these findings may be linked to differences in the type of PXR employed (human vs. mouse) or in the in vivo vs. in vitro nature of the experiments. Such results may also indicate that subcellular trafficking is an important regulatory process that tunes the function of this nuclear xenobiotic receptor.

Ligand Binding
The PXRs from a variety of species are all promiscuous and can bind to a variety of chemically and structurally distinct xenobiotic and endobiotic compounds. As measured by scintillation binding assays (32) and coactivator receptor ligand assays (CARLA, a ligand-dependent coregulator recruitment assay) (43), PXR is activated by the direct binding of ligands within the receptor’s ligand-binding cavity (2). PXR agonists include natural and synthetic steroids such as 5ß-pregnane-3,20-dione and estradiol (32), and xenobiotics like the cholesterol drugs lovastatin and SR12813 (6, 32), the anticancer drugs tamoxifen and taxol (7, 44), the antibiotic rifampicin (1, 6), and the active agent of St. John’s wort, hyperforin (45, 46). These ligands vary widely in shape and chemical features and range in mass from 250 to greater than 800 Da. Clearly, PXR has a binding promiscuity unlike that of any other member of the NR superfamily (2). Crystallographic studies of PXR have revealed a novel insert in the LBD along with a large and conformable binding pocket (13, 27, 47). These structures offer valuable insight into both the promiscuity and specificity of the receptor, as discussed below.

Heterodimerization with RXR
Like many other NRs, PXR controls transcriptional events as a heterodimer with RXR{alpha}. PXR is known to bind to at least four distinct DNA response elements, including both direct and everted repeats. Several other receptors that form heterodimers with RXR{alpha} also utilize both DR and ER response elements, including CAR, the vitamin D receptor, and the thyroid hormone receptor (48, 49). Thus, because the LBDs of RXR{alpha} and these partner receptors are expected to form only one type of heterodimer (50), the linkers connecting the DBDs and LBDs of these receptors must be flexible to bind to distinctly oriented DNA response elements. It is also possible that alternative DNA binding modes may influence coregulator recruitment and transcriptional activity in a ligand- and/or tissue-specific manner, providing another level of regulation of PXR action (51).

Coregulator Binding
PXR was initially found to interact with SRC-1 (also known as nuclear receptor coactivator 1) (4), a member of the p160 family of coactivators that bind in a ligand-dependent manner to NRs using Leu-X-X-Leu-Leu repeats (where X is any amino acid) (52, 53, 54, 55, 56). Crystal structures of several NR LBDs in complex with coactivator fragments have revealed that binding of ligand induces a conformational change in the activation function 2 (AF-2) region at the C terminus of the NR LBD to create a coactivator-binding cleft (47, 50, 57, 58, 59). This interaction will be studied in further detail later in this review (60). Other members of the p160 coactivator family known to interact with PXR include transcriptional intermediary factor 2/glucocorticoid receptor-interacting protein 1/nuclear receptor coactivator 2 (61) and p300/cointegrating protein/activator of thyroid and retinoic acid receptor/amplified in breast cancer 1/thyroid hormone receptor activator molecule 1/receptor-associated coactivator 3 (24). Binding of a coactivator protein results in the recruitment of basal transcription factors, such as cAMP response element binding protein-binding protein/p300 (53, 62), as well as histone acetyltransferases that remodel chromatin to enhance transcription (63, 64). SRC-1 also recruits coactivator-associated arginine methyltransferase 1, an arginine methyltransferase that methlyates histone H3 to loosen chromatin for transcription (65, 66). Other coactivators known to interact functionally with PXR include receptor interacting protein 140 (67, 68), Suppressor for Gal 1 SUG-1 (67), peroxisome proliferator-activated receptor-binding protein PBP (69), and the peroxisome proliferator activating receptor {gamma} coactivator PGC-1 (70). Several transcriptional corepressors that down-regulate gene expression have also been found to bind PXR. Among these are silencing mediator of retinoid thyroid receptor (7), nuclear receptor corepressor (7, 69, 71), and, most recently, the small heterodimer partner (72). Unraveling the structural basis of the recruitment of coregulators to NR-DNA complexes remains a critical area for future study.


    MOBILITY IN PXR STRUCTURE
 TOP
 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 
Several crystal structures of the LBD of PXR have been determined in the unliganded (apo) state and in complex with activating ligands and fragments of transcriptional coregulators. Published structures include the PXR LBD bound to the cholesterol-lowering drug SR12813, both in the presence and absence of SRC-1 peptide, in complex with hyperforin, the psychoactive agent found in the herbal antidepressant St. John’s Wort, and in complex with the macrolide antibiotic rifampicin (13, 27, 47, 73, 74, 75) (Table 1Go). The overall fold of PXR consists of a three-layered {alpha}-helical sandwich ({alpha}1–{alpha}3/{alpha}4–{alpha}5–{alpha}8–{alpha}9/{alpha}7–{alpha}10) that encloses a large, conformable binding pocket (Fig. 1Go). A five-stranded antiparallel ß-sheet (ß2, ß3, ß4, ß1, and ß1') lies adjacent to the ligand-binding pocket. This extended ß-sheet is unique to PXR, as NR LBDs typically contain only two- or three-stranded ß-sheets (57, 76, 77, 78, 79). The PXR LBD ends with a short helix ({alpha}AF) critical to the AF-2 region of the receptor that contacts transcriptional coregulators (27).


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Table 1. Comparison of Human and Mouse EC50 Values and the Key Residues Contacted in the Crystal Structure of PXR in Complex with Three Structurally and Chemically Disparate Ligands: SR12813, Hyperforin, and Rifampicin

 


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Fig. 1. Structure of the PXR LBD (Blue) in Complex with the Small Agonist SR12813 (Red) and a Fragment of the SRC-1 Transcriptional Coactivator (Cyan) (47 )

The 60-residue sequence insert novel to the PXRs and central to the receptor’s promiscuity is highlighted in magenta.

 
The {alpha}-helical portion of PXR is similar in structure to the NR LBDs described previously, with root-mean-square deviations in C{alpha} positions of 1.8–2.9 Å (80, 81, 82). Where PXR deviates most significantly in structure, and what likely contributes critically to its promiscuous ability to respond to chemically distinct ligands, is at the bottom of the LBD, as shown in Fig. 1Go. The PXRs contain an insert of approximately 60 residues that is unique in the NR superfamily. This insert, amino acids 177–228 in human PXR, contains not only the ß1-ß1' regions that extend the PXR ß-sheet to five strands, but also a novel {alpha}2 that folds along the underside of the expansive PXR ligand-binding pocket (73). A portion of this sequence insert (residues 178–191) has been disordered in the PXR LBD structures examined to date (13, 27, 47, 73, 75). Thus, the PXRs line their ligand-binding pockets with novel secondary structural elements, including {alpha}2 and ß1-ß1', many of which are structurally flexible (Fig. 2Go).



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Fig. 2. Sequence Alignment of the PXR LBDs from Various Species

Secondary structural elements of human PXR are indicated. Residues lining the binding pocket are denoted by a caret; residues lining the pocket determined to be important to species-specific activation are indicated by an asterisk. The dotted line identifies residues that are disordered in all the PXR LBD crystal structures determined to date. Shaded areas indicate regions observed to be disordered in the PXR-rifampicin complex structure. {alpha}AF, Activation function helix.

 
The conformability of key regions of the PXR LBD is critical to the ability of the receptor to bind to compounds of varying size and shape. The recent structure of PXR in complex with the large macrolide antibiotic rifampicin has provided a direct observation of the importance of flexibility in receptor ligand binding. When the apo structure of the PXR LBD was first reported in 2001, it was noted that the receptor’s binding pocket, although large, was not large enough to accommodate the established PXR agonist rifampicin (27). The subsequent determination of the PXR-rifampicin complex structure reveals that three regions of the LBD become disordered to create the space necessary for this 823-Da agonist to bind. These regions are the flexible loop formed by residues 229–235, a mobile hydrophobic loop from residues 309–321, and the approximately 192–210 stretch that is a bona fide helix in some structures, but a partially ordered pseudohelix in others (Fig. 3Go). Each of these regions (indicated in yellow in Fig. 3Go) is highly mobile and exhibits no clear electron density in this 2.8-Å resolution crystal structure of the PXR-LBD in complex with rifampicin. Similarly, the piperidino group on rifampicin expected to lie next to the approximately 192–210 loop also lacked clear electron density (73). These observations show that PXR can bind effectively to ligands and up-regulate gene expression even when a significant portion of its ligand-binding pocket is unstructured. These results also establish that the mobility of regions of PXR that are novel in the NR family is vital to the promiscuous ligand binding character of this xenobiotic receptor.



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Fig. 3. Close-up of the PXR-LBD Bound to the Large Macrolide Antibiotic Rifampicin (Green and Red) (73 )

Regions of the structure disordered in this complex are highlighted in yellow. The same regions are observed to be mobile in other PXR-LBD structures and to conform to the presence of distinct ligands and bound coactivator fragments.

 
Residues 309–321 were traced as a loop in the apo and in the SR12813 complexes (27) but adopt an {alpha}- helical structure in complexes with hyperforin, rifampicin, and SR12813 with the SRC-1 coactivator peptide (13, 47, 73). This helix, designated {alpha}6, is different from {alpha}6 helices found in other NRs, which are positioned at the bottom of the ligand-binding cavity in the same region where the approximately 192–210 residues are located in PXR. Residues 229–235 support the position of the 192–210 region, and their flexibility mirrors that of the longer region nearby. The stretch from about 192–210 was pseudohelical in the initial apo- and SR12813-bound structures, but folded into {alpha}2 in the structures of PXR bound to hyperforin and the combination of SR12813 and the SRC-1 peptide. This region of the receptor directly contacts bound ligands and changes its position to conform to specific ligands; thus, this novel structural motif is central to the ligand binding promiscuity exhibited by the PXRs.

Even when they are not disordered, these regions of the PXR LBD are mobile and have been observed to change position to enhance contacts with distinctly shaped ligands. Between the apo- and rifampicin-bound structures, for example, the {alpha}6, 229–235, and 204–210 regions of the receptor exhibit main-chain shifts of 1.5 Å, 3.2 Å, and 4.5 Å, respectively, and side chain displacements of up to 7 Å (Fig. 4Go). This conformability allows the ligand-binding pocket of PXR to expand from 1280 Å (3) in volume in the SR12813 complex to more than 1600 Å3 in other structures (13, 27, 47, 73).



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Fig. 4. Schematic Representation of the Ligand-Binding Pocket of human PXR, with Residues that Remain Static in Structure in Bold and Those That Exhibit Less Than 1 Å Shifts in Position in Italics

The side chains of residues that move more than 1 Å in position are shown, along with the magnitude of maximal shifts observed upon ligand binding. Note that four of the seven residues that exhibit a high degree of ligand-induced structural flexibility are part of the sequence insert novel to the PXRs.

 
In addition to mobility, which allows the pocket to accommodate a variety of ligands, PXR’s {alpha}2 may have another function. It is not clear how ligands enter and exit the ligand-binding pocket of this promiscuous receptor. In the peroxisome proliferator-activating receptors (50, 57), the putative ligand entrance path occurs in a region blocked by {alpha}6 in PXR. The flexible and untethered {alpha}2 may function as a trapdoor in PXR, dropping out of the way so that ligands can enter the binding pocket. In some PXR structures, a solvent accessible channel of up to 3 Å wide and 9 Å long is present in the area adjacent to {alpha}2 (13, 27, 47). Thus, the sequence motif that contains {alpha}2 appears to plays a dual role in receptor function: conforming to distinct ligand shapes to enhance promiscuity and providing a dynamic entry and exit pathway for ligand binding and dissociation.

There are six amino acid side chains that are consistently involved in ligand binding in all PXR LBD structures determined to date: three polar residues (Ser-247, Gln-285, and His-407) and three hydrophobic residues (Met-243, Trp-299, and Phe-420) (Fig. 4Go) (13, 27, 47, 73). The directed promiscuity exhibited by the different species of PXR may be attributed partly to changes in these binding residues. For example, the residues Gln-285, His-407, and Met-243 are not conserved in mouse PXR. This receptor shows a lesser degree of promiscuity and shows no or minimal activity with SR12813, hyperforin, or rifampicin (Table 1Go). A similar trend is seen in zebra fish PXR. Alignments of mammalian PXRs (Fig. 2Go) reveal that the highest degree of sequence identity occurs between the human and rhesus receptor (96%); notably, the same six binding residues are conserved, and both receptors respond largely to the same pool of compounds (83). Differences in diet were originally thought to be the driving force for PXR’s directed promiscuity. It has recently been hypothesized, however, that bile acids served as the key evolutionary ligands that drove the receptor’s increasing degree of promiscuity over time (84).

NR LBDs typically contain AF-2 regions that bind to LxxLL motifs in transcriptional coactivators, and I/LxxI/VI motifs in corepressors (85). The structure of the human PXR LBD has been determined in complex with the second LxxLL motif of the coactivator SRC-1 bound to the receptor’s AF-2 region. The LxxLL motif forms an {alpha}-helix, with a second short helix kinked perpendicular to the first (Fig. 5Go). The leucines in the LxxLL motif pack via hydrophobic contacts against the surface of PXR in a groove formed by {alpha}3, {alpha}4, and {alpha}AF. A charge clamp involving PXR residues Lys-259 and Glu-427 stabilizes the weak helix dipole at the C and N termini, respectively, of the LxxLL motif (47, 57). Charged residues are conserved in these positions in NR LBDs and are receptor-coactivator interactions.



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Fig. 5. An LxxLL Motif of the Human Coactivator SRC-1 (Residues 682–296; Magenta) Bound to the AF-2 Region of PXR (White) via a Combination of Nonpolar and Electrostatic Contacts.

 
The structure of the PXR LBD in complex with the SR12813 ligand alone revealed three distinct binding modes for this small agonist within the receptor’s pocket. A subsequent structure with PXR in complex with both SR12813 and a fragment of SRC-1, however, revealed only a single, distinct orientation of the ligand. This observation suggests that the PXR LBD breathes, allowing small ligands to sample multiple binding modes. In the presence of a bound coactivator fragment, however, this sampling motion is restricted, resulting in stabilization of the ligand into a single conformation (47).

Numerous single-site mutations have been introduced into the PXR LBD with varying effects on basal transcriptional activity. Some of these mutations lead to variant receptors that exhibit increased basal activation, including H407N, S247W, W299A, and R410A (73). In the S247W mutation, the replacement of serine with a bulky tryptophan residue is expected to fill the pocket to mimic ligand binding. This may stabilize coactivator interactions and increase basal transcriptional activity. The structural basis for the effects of other mutations, however, is less clear. For example, H407N and W299A may impact receptor activity by impairing corepressor binding or by improving coactivator binding. Conversely, the mutation of charged residues (R410N, D205A, E321A, and R413A) may facilitate increased corepressor or decreased coactivator binding, causing the partial or complete loss of basal activation.


    AREAS FOR FUTURE STUDY
 TOP
 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 
In just a few years, PXR has moved from an orphan receptor to an adopted central xenobiotic sensor and a putative drug target. We now face new challenges to deepen our understanding of the basic functions of PXR in human biology, as well as how the receptor might be harnessed in a clinical setting. The role that distinct ligands play in PXR’s regulation of tissue- and coregulator-specific transcription events is emerging as a key area of study for this xenobiotic receptor (86). In addition, the potential impact of sites of phosphorylation on the action and stability of this and other NRs warrants detailed attention (69), as does the pursuit of structures of full-length PXR-RXR heterodimers on DNA. Finally, because PXR is up-regulated in certain human cancers (87, 88), the search for selective PXR modulators might provide novel therapeutic tools for the treatment of neoplastic and metabolic diseases.


    ACKNOWLEDGMENTS
 
We thank members of the Redinbo Laboratory, particularly Ryan Watkins, Jill Chrencik, Schroeder Noble, Yu Xue, V.A. Carnahan, and Eric Ortlund, for considerable intellectual input regarding NR structure and function. We also thank Steve Kliewer, Bruce Wisely, Linda Moore, Tim Willson, Jon Collins, Mill Lambert, David Moore, Elizabeth Wilson, and Donald McDonnell for numerous stimulating discussions regarding PXR and NR action.


    FOOTNOTES
 
First Published Online June 16, 2005

Abbreviations: AF-2, Activation function 2; CAR, constitutive androstane receptor; CYP450, cytochrome P450; DBD, DNA-binding domain; DR, direct repeat; ER, everted repeat; LBD, ligand-binding domain; NR, nuclear receptor; PCN, pregnenolone 16-{alpha}-carbonitrile; PXR, pregnane X receptor; RXR, retinoic X receptor; SRC, steroid receptor coactivator;

Received for publication April 18, 2005. Accepted for publication June 10, 2005.


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 PXR FUNCTION
 MOBILITY IN PXR STRUCTURE
 AREAS FOR FUTURE STUDY
 REFERENCES
 

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