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Publication Abstract from PubMed

Peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1alpha) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1alpha binding partners is Liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1alpha is known to bind and activate LRH-1, mechanisms through which PGC1alpha changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1alpha complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1alpha 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-PGC1alpha complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1alpha 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 PGC1alpha but promoted allosteric signaling from the Helix 6/beta-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1alpha interaction and may illuminate strategies for selective therapeutic targeting of PGC1alpha-dependent LRH-1 signaling pathways.

Structure and Dynamics of the Liver Receptor Homolog 1-PGC1alpha Complex.,Mays SG, Okafor CD, Tuntland ML, Whitby RJ, Dharmarajan V, Stec J, Griffin PR, Ortlund EA Mol Pharmacol. 2017 Mar 31. pii: mol.117.108514. doi: 10.1124/mol.117.108514. PMID:28363985^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.