PDBsum entry 1pk5

Gene regulation

PDB id: 1pk5

Contents

Protein chains

242 a.a. *

Waters ×158

* Residue conservation analysis

PDB id:

1pk5

Name:

Gene regulation

Title:

Crystal structure of the orphan nuclear receptor lrh-1

Structure:

Orphan nuclear receptor nr5a2. Chain: a, b. Fragment: lrh-1 lbd. Synonym: liver receptor homolog, lrh-1. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Gene: nr5a2 or lrh1. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.40Å R-factor: 0.208 R-free: 0.235

Authors:

E.P.Sablin,I.N.Krylova,R.J.Fletterick,H.A.Ingraham

Key ref:

E.P.Sablin et al. (2003). Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Mol Cell, 11, 1575-1585. PubMed id: 12820970 DOI: 10.1016/S1097-2765(03)00236-3

Date:

04-Jun-03 Release date: 01-Jul-03

Protein chains

P45448  (NR5A2_MOUSE) -  Nuclear receptor subfamily 5 group A member 2 from Mus musculus

Seq: 560 a.a.

Struc: 242 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/S1097-2765(03)00236-3

Mol Cell 11:1575-1585 (2003)

PubMed id: 12820970

Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1.

E.P.Sablin, I.N.Krylova, R.J.Fletterick, H.A.Ingraham.

ABSTRACT

The orphan nuclear receptors SF-1 and LRH-1 are constitutively active, but it remains uncertain whether their activation is hormone dependent. We report the crystal structure of the LRH-1 ligand binding domain to 2.4 A resolution and find the receptor to be a monomer that adopts an active conformation with a large but empty hydrophobic pocket. Adding bulky side chains into this pocket resulted in full or greater activity suggesting that, while LRH-1 could accommodate potential ligands, these are dispensable for basal activity. Constitutive LRH-1 activity appears to be conferred by a distinct structural element consisting of an extended helix 2 that provides an additional layer to the canonical LBD fold. Mutating the conserved arginine in helix 2 reduced LRH-1 receptor activity and coregulator recruitment, consistent with the partial loss-of-function phenotype exhibited by an analogous SF-1 human mutant. These findings illustrate an alternative structural strategy for nuclear receptor stabilization in the absence of ligand binding.

Selected figure(s)

Figure 1.
Figure 1. Structure of LRH-1 Ligand Binding Domain(A and B) Ribbon representation of LRH-1 structure shows α helices and β strands forming four layers in the LRH-1 structure as highlighted with orange, purple, pink, and red, respectively. The view on (B) is rotated vert, similar 90° relative to that shown in (A). The LRH-1 specific helix H2 (red) forms the fourth and outmost layer in the structure.(C) Superposition of LRH-1 with the RXRα LBD bound to ligand (PDB entry 1FBY) depicts LRH-1 in orange and RXRa with 9-cis-retinoic acid in blue.

Figure 6.
Figure 6. The Role of Helix H2 in Stabilizing and Activating LRH-1(A) Residues at the interface between helix H2 and H3 are indicated, and those that are conserved between LRH-1 and SF-1 are underlined. The position of the conserved arginine R352 that is mutated in the SF-1 R255L human patient is circled.(B) Activity of wild-type LRH-1 (black bars) or the R352E mutant (gray bars) was measured using the AroLuc reporter in HepG2 cells, with or without increasing concentrations of mouse corepressor SHP (+SHP) or the coactivator human GRIP1 (+GRIP).

The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 11, 1575-1585) copyright 2003.

Figures were selected by an automated process.