1ZGY: Structural And Biochemical Basis For Selective Repression Of The Orphan Nuclear Receptor Lrh-1 By Shp

Citation:
Abstract
The functional interaction between the orphan nuclear receptors small heterodimer partner (SHP) and liver receptor homolog 1 (LRH-1), where SHP binds to LRH-1 and represses its constitutive transcriptional activity, is crucial for regulating genes involved in cholesterol homeostasis. Here, we report structural and biochemical analyses of the LRH-1/SHP interaction. The crystal structure and modeling studies of the LRH-1 ligand-binding domain bound to either of the two LXXLL-related motifs of SHP show that the receptor undergoes conformational changes to accommodate the SHP docking and reveal key residues that determine the potency and selectivity of SHP binding. Through a combination of mutagenesis and binding studies, we demonstrate that only the second SHP LXXLL motif is required for repressing LRH-1, and this motif displays a strong preference for binding to LRH-1 over the closely related receptor steroidogeneic factor 1 (SF-1). Structural comparisons indicate that this binding selectivity is determined by residues flanking the core LXXLL motifs. These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor/coregulator selectivity is achieved.
PDB ID: 1ZGYDownload
MMDB ID: 34316
PDB Deposition Date: 2005/4/22
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.8  Å
Source Organism:
Rattus norvegicus
Similar Structures:
Biological Unit for 1ZGY: dimeric; determined by author and by software (PISA)
Molecular Components in 1ZGY
Label Count Molecule
Proteins (2 molecules)
1
Peroxisome Proliferator Activated Receptor Gamma(Gene symbol: PPARG)
Molecule annotation
1
Nuclear Receptor Subfamily 0, Group B, Member 2(Gene symbol: Nr0b2)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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