1NRL

Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813

Summary for 1NRL

• Entry DOI: 10.2210/pdb1nrl/pdb
• Related: 1ILG 1ILH 1M13
• Descriptor: Orphan nuclear receptor PXR, Nuclear Receptor Coactivator 1 isoform 3, [2-(3,5-DI-TERT-BUTYL-4-HYDROXY-PHENYL)-1-(DIETHOXY-PHOSPHORYL)-VINYL]-PHOSPHONIC ACID DIETHLYL ESTER, ... (4 entities in total)
• Functional Keywords: nuclear receptor, coactivator, pxr, xenobiotic, src-1, ligand binding domain, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: O75469
• Total number of polymer chains: 4
• Total formula weight: 79183.13

Authors

Watkins, R.E.,Davis-Searles, P.R.,Lambert, M.H.,Redinbo, M.R. (deposition date: 2003-01-25, release date: 2003-08-19, Last modification date: 2024-02-14)

Primary citation

Watkins, R.E.,Davis-Searles, P.R.,Lambert, M.H.,Redinbo, M.R.
Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor
J.Mol.Biol., 331:815-828, 2003

PubMed Abstract: The pregnane X receptor (PXR) detects the presence of a wide variety of endogenous and xenobiotic compounds, and is a master regulator of the expression of genes central to drug metabolism and excretion. We present the 2.0A crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif. PXR crystallizes as a homodimer in the asymmetric unit in this structure and possesses a novel alpha2 helix adjacent to its ligand-binding cavity. The SRC-1 peptide forms two distinct helices and binds adjacent to the ligand-dependent transactivation AF-2 helix on the surface of PXR. In contrast with previous PXR structures, in which SR12813 bound in multiple orientations, the small SR12813 agonist in this structure binds in a single, unique orientation within the receptor's ligand-binding pocket and contacts the AF-2 helix. Thermal denaturation studies reveal that the SR12813 ligand and SRC-1 coactivator peptide each stabilize the LBD of PXR, and that together they exert an additive effect on the stability of the receptor. These results indicate that the binding of coactivator to the surface of PXR limits the ability of this promiscuous receptor to "breathe" and helps to trap a single, active conformation of SR12813. They further reveal that specificity is required for PXR activation.

PubMed: 12909012
DOI: 10.1016/S0022-2836(03)00795-2

Experimental method

X-RAY DIFFRACTION (2 Å)