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PDBsum entry 1ilh
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Gene regulation
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PDB id
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1ilh
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Contents |
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* Residue conservation analysis
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DOI no:
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Science
292:2329-2333
(2001)
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PubMed id:
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The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
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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.
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ABSTRACT
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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.
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Selected figure(s)
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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.
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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).
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The above figures are
reprinted
by permission from the AAAs:
Science
(2001,
292,
2329-2333)
copyright 2001.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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I.Bailey,
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A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.
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PLoS One,
6,
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J.Cheng,
X.Ma,
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(2011).
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Br J Pharmacol,
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Production of protein complexes via co-expression.
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Protein Expr Purif,
75,
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(2011).
Byakangelicin induces cytochrome P450 3A4 expression via transactivation of pregnane X receptors in human hepatocytes.
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PLoS One,
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PDB code:
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L.C.Mota,
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and
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Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment.
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Toxicol Appl Pharmacol,
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PDB code:
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PDB codes:
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S.Kortagere,
D.Chekmarev,
W.J.Welsh,
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The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation.
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Drug Metab Dispos,
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W.Wang,
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and
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(2008).
Construction and characterization of a fully active PXR/SRC-1 tethered protein with increased stability.
|
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Protein Eng Des Sel,
21,
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PDB codes:
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A.Martínez,
A.Márquez,
J.Mendoza,
C.Taxonera,
M.Fernández-Arquero,
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E.G.de la Concha,
and
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|
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C.B.Pollock,
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(2007).
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|
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
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only a partial list as not all journals are covered by
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so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
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shown on the right.
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|
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