5UNJ

Structure of Human Liver Receptor Homolog 1 in complex with PGC1a and RJW100

Summary for 5UNJ

• Entry DOI: 10.2210/pdb5unj/pdb
• Descriptor: Nuclear receptor subfamily 5 group A member 2, Peroxisome proliferator-activated gamma coactivator 1-alpha, (1R,3aR,6aR)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-ol, ... (4 entities in total)
• Functional Keywords: nuclear receptor, agonist, coregulator, nuclear protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30241.12

Authors

Mays, S.G.,Ortlund, E.A. (deposition date: 2017-01-31, release date: 2017-04-19, Last modification date: 2023-10-04)

Primary citation

Mays, S.G.,Okafor, C.D.,Tuntland, M.L.,Whitby, R.J.,Dharmarajan, V.,Stec, J.,Griffin, P.R.,Ortlund, E.A.
Structure and Dynamics of the Liver Receptor Homolog 1-PGC1 alpha Complex.
Mol. Pharmacol., 92:1-11, 2017

PubMed Abstract: Peroxisome proliferator-activated gamma coactivator 1- (PGC1) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1 binding partners is liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1 is known to bind and activate LRH-1, mechanisms through which PGC1 changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1 complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1 with higher affinity than to the coactivator, nuclear receptor coactivator-2 (Tif2), in coregulator peptide recruitment assays. We present the first crystal structure of the LRH-1-PGC1 complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1 induced correlated atomic motion throughout the entire LRH-1 activation function surface, which was dependent on charge-clamp formation. In contrast, Tif2 induced weaker signaling at the activation function surface than PGC1 but promoted allosteric signaling from the helix 6/-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1 interaction and may illuminate strategies for selective therapeutic targeting of PGC1-dependent LRH-1 signaling pathways.

PubMed: 28363985
DOI: 10.1124/mol.117.108514

Experimental method

X-RAY DIFFRACTION (1.959 Å)