TY - JOUR T1 - Structure and Dynamics of the Liver Receptor Homolog 1-PGC1α Complex JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.108514 SP - mol.117.108514 AU - Suzanne G Mays AU - C Denise Okafor AU - Micheal L Tuntland AU - Richard J Whitby AU - Venkatasubramanian Dharmarajan AU - Jozef Stec AU - Patrick R Griffin AU - Eric A Ortlund Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/03/31/mol.117.108514.abstract N2 - Peroxisome proliferator-activated gamma coactivator 1-α (PGC1α) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1α binding partners is Liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1α is known to bind and activate LRH-1, mechanisms through which PGC1α changes LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1α complex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1α 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-PGC1α complex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1α 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 PGC1α but promoted allosteric signaling from the Helix 6/β-sheet region of LRH-1 to the activation function surface. These studies are the first to probe mechanisms underlying the LRH-1-PGC1α interaction and may illuminate strategies for selective therapeutic targeting of PGC1α-dependent LRH-1 signaling pathways. ER -