Structure and dynamics of the liver receptor homolog 1-PGC1α complex

Suzanne G. Mays, C. Denise Okafor, Micheal L. Tuntland, Richard J. Whitby, Venkatasubramanian Dharmarajan, Józef Stec, Patrick R. Griffin, Eric A. Ortlund

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalMolecular pharmacology
Volume92
Issue number1
DOIs
StatePublished - Jul 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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