1ILH

Crystal Structure of Human Pregnane X Receptor Ligand Binding Domain Bound to SR12813

Summary for 1ILH

• Entry DOI: 10.2210/pdb1ilh/pdb
• Related: 1ILG
• Descriptor: ORPHAN NUCLEAR RECEPTOR PXR, [2-(3,5-DI-TERT-BUTYL-4-HYDROXY-PHENYL)-1-(DIETHOXY-PHOSPHORYL)-VINYL]-PHOSPHONIC ACID DIETHLYL ESTER (3 entities in total)
• Functional Keywords: nuclear receptor, multiple binding modes, xenobiotic, promiscuous, ligand, gene regulation
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : O75469
• Total number of polymer chains: 1
• Total formula weight: 36785.40

Authors

Watkins, R.E.,Redinbo, M.R. (deposition date: 2001-05-08, release date: 2001-06-27, Last modification date: 2023-08-16)

Primary citation

Watkins, R.E.,Wisely, G.B.,Moore, L.B.,Collins, J.L.,Lambert, M.H.,Williams, S.P.,Willson, T.M.,Kliewer, S.A.,Redinbo, M.R.
The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
Science, 292:2329-2333, 2001

PubMed Abstract: The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.

PubMed: 11408620
DOI: 10.1126/science.1060762

Experimental method

X-RAY DIFFRACTION (2.76 Å)