PDBsum entry 1ilh

Gene regulation

PDB id

1ilh

Contents

			Protein chain

					270 a.a. *

			Ligands

					SRL

			Waters ×166

* Residue conservation analysis

References listed in PDB file

Key reference

Title

The human nuclear xenobiotic receptor pxr: structural determinants of directed promiscuity.

Authors

R.E.Watkins, G.B.Wisely, L.B.Moore, J.L.Collins, M.H.Lambert, S.P.Williams, T.M.Willson, S.A.Kliewer, M.R.Redinbo.

Ref.

Science, 2001, 292, 2329-2333. [DOI no: 10.1126/science.1060762]

PubMed id

11408620

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.



	Figure 1. Fig. 1. (A) Structure of the LBD of the human xenobiotic receptor PXR. Residues 142 to 177 and 198 to 431 of hPXR in complex with three orientations of SR12813 are shown; helices are in red and strands are in green, including the two novel strands, 1 and 1' that complete the five-stranded antiparallel sheet observed in this structure. Secondary structural elements are numbered according to the RXR structure (19). See also Web fig. 1 (25). (B) hPXR-LDB electron density: unbiased (F[obs] F[calc]) electron density into which the novel 1/ 1' strands (residues 210 to 228) of hPXR were traced (2.75 Å resolution, contoured at 1.2 ). (C and D) The ligand-binding cavity of hPXR. A cutaway view of the binding cavity, including electrostatic surface potentials (positive in blue, negative in red), reveals a relatively smooth, uncharged surface. The cavity is enclosed by portions of five helices ( 3, 5, 7, 10, and AF), three strands ( 1, 3, and 4), and three loops (the 10- AF region and the two mobile regions between 4 and 7 and from residue 198 to 1). Select residues lining the cavity are indicated. In particular, the positions of the following polar residues that contact SR12813 are indicated in red: Ser208, Ser247, Gln285, His407, and Arg410. Regions of the surface 309-321 loop, which may facilitate the expansion of the ligand-binding pocket, are also shown, including the conserved hydrophobic residues Phe^315, Leu318, Leu319, and Leu320.		Figure 2. Fig. 2. Three experimentally observed positions of SR12813 in the ligand-binding pocket of hPXR. Intermolecular interactions are shown with amino acid side chains in blue and the C atom as a sphere. The positions 1, 2, and 3 of SR12813 are rendered in cyan, purple, and orange, respectively. Equivalent side chains from the apo structure are shown in white. A small number of residues undergo rotamer shifts (Met243, Cys284, and His407) or small shifts in position (Ser208 and Leu209) upon SR12813 binding. Residues mutated to examine the specificity of mouse PXR are underlined. (A) Position 1 makes van der Waals contacts with eight side chains, and forms one 3.0 Å hydrogen bond with Ser247. (B) Position 2 makes van der Waals contacts with seven side chains, and forms one 2.8 Å hydrogen bond with His407. (C) Position 3 makes van der Waals contacts with six side chains, and forms three hydrogen bonds with Ser247, Gln285, and Ser208, which forms a water-mediated hydrogen bond. See also Web table 2 and Web fig. 2 (25).

PROCHECK

	Headers