| Structural highlights
Function
NR1I2_HUMAN Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
The ligand-binding domain (LBD) of the human nuclear receptor pregnane X receptor (PXR) is known to crystallize in two different crystal forms, P2(1)2(1)2(1) or P4(3)2(1)2, depending on the construct and the strategy used for protein production, as well as the presence or absence of the coactivator-derived peptide SRC-1. In order to facilitate biophysical and structural studies, a versatile construct was designed that allows access to both forms. This was achieved by introducing a thrombin cleavage site between the PXR(LBD) and the SRC-1 peptide fused to its C-terminus. Here, we describe the expression, purification and crystallization processes of this novel construct and report two new structures of PXR(LBD) that were obtained thanks to this strategy.
A two-in-one expression construct for biophysical and structural studies of the human pregnane X receptor ligand-binding domain, a pharmaceutical and environmental target.,Carivenc C, Laconde G, Blanc P, Amblard M, Bourguet W, Delfosse V Acta Crystallogr F Struct Biol Commun. 2025 Mar 1. doi: , 10.1107/S2053230X2500069X. PMID:39923198[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest. 1998 Sep 1;102(5):1016-23. PMID:9727070 doi:10.1172/JCI3703
- ↑ Zhang J, Kuehl P, Green ED, Touchman JW, Watkins PB, Daly A, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Wrighton SA, Hancock M, Kim RB, Strom S, Thummel K, Russell CG, Hudson JR Jr, Schuetz EG, Boguski MS. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics. 2001 Oct;11(7):555-72. PMID:11668216
- ↑ Geick A, Eichelbaum M, Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem. 2001 May 4;276(18):14581-7. Epub 2001 Jan 31. PMID:11297522 doi:10.1074/jbc.M010173200
- ↑ Li Y, Ross-Viola JS, Shay NF, Moore DD, Ricketts ML. Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr. 2009 May;139(5):898-904. doi: 10.3945/jn.108.103572. Epub 2009 Mar 18. PMID:19297428 doi:10.3945/jn.108.103572
- ↑ Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, Lambert MH, Kliewer SA, Redinbo MR. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry. 2003 Feb 18;42(6):1430-8. PMID:12578355 doi:10.1021/bi0268753
- ↑ Teotico DG, Bischof JJ, Peng L, Kliewer SA, Redinbo MR. Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Mol Pharmacol. 2008 Dec;74(6):1512-20. doi: 10.1124/mol.108.050732. Epub 2008 Sep, 2. PMID:18768384 doi:10.1124/mol.108.050732
- ↑ Carivenc C, Laconde G, Blanc P, Amblard M, Bourguet W, Delfosse V. A two-in-one expression construct for biophysical and structural studies of the human pregnane X receptor ligand-binding domain, a pharmaceutical and environmental target. Acta Crystallogr F Struct Biol Commun. 2025 Mar 1. PMID:39923198 doi:10.1107/S2053230X2500069X
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