1ZGY

Structural and Biochemical Basis for Selective Repression of the Orphan Nuclear Receptor LRH-1 by SHP

Summary for 1ZGY

• Entry DOI: 10.2210/pdb1zgy/pdb
• Descriptor: Peroxisome proliferator activated receptor gamma, Nuclear receptor subfamily 0, group B, member 2, 2,4-THIAZOLIDIINEDIONE, 5-[[4-[2-(METHYL-2-PYRIDINYLAMINO)ETHOXY]PHENYL]METHYL]-(9CL), ... (4 entities in total)
• Functional Keywords: protein-peptide complex, transcription
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P37231; Cytoplasm : P97947
• Total number of polymer chains: 2
• Total formula weight: 33301.76

Authors

Li, Y.,Choi, M.,Suino, K.,Kovach, A.,Daugherty, J.,Kliewer, S.A.,Xu, H.E. (deposition date: 2005-04-22, release date: 2005-07-26, Last modification date: 2023-08-23)

Primary citation

Li, Y.,Choi, M.,Suino, K.,Kovach, A.,Daugherty, J.,Kliewer, S.A.,Xu, H.E.
Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner.
Proc.Natl.Acad.Sci.Usa, 102:9505-9510, 2005

PubMed 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.

PubMed: 15976031
DOI: 10.1073/pnas.0501204102

Experimental method

X-RAY DIFFRACTION (1.8 Å)