Research update
The PXR crystal structure: the end of the beginning

https://doi.org/10.1016/S0165-6147(02)01977-6Get rights and content

Abstract

The pregnane X receptor (PXR) has a key role in the regulation of both drug metabolism and drug efflux by activating the expression of genes encoding cytochrome P450 enzymes and drug efflux transporters, respectively. Thus, coadministration of a PXR ligand and drugs handled by such enzymes or transporters leads to drug interactions. The need to identify drugs in development with the least potential to cause adverse drug interactions has led to the recent solving of the crystal structure of the human PXR ligand binding domain.

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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(Present address: Concurrent Pharmaceuticals, One Broadway, 14th Floor, Cambridge, MA 02142, USA.)

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