title: Structure and Dynamics of the Liver Receptor Homolog 1-PGC1αComplex.
abstract: Peroxisome proliferator-activated gamma coactivator 1-α(PGC1α) regulates energy metabolism by directly interacting with transcription factors to modulate gene expression. Among the PGC1αbinding partners is liver receptor homolog 1 (LRH-1; NR5A2), an orphan nuclear hormone receptor that controls lipid and glucose homeostasis. Although PGC1αis known to bind and activate LRH-1, mechanisms through which PGC1αchanges LRH-1 conformation to drive transcription are unknown. Here, we used biochemical and structural methods to interrogate the LRH-1-PGC1αcomplex. Purified, full-length LRH-1, as well as isolated ligand binding domain, bound to PGC1αwith 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-PGC1αcomplex, which depicts several hydrophobic contacts and a strong charge clamp at the interface between these partners. In molecular dynamics simulations, PGC1αinduced 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 PGC1αbut 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-PGC1αinteraction and may illuminate strategies for selective therapeutic targeting of PGC1α-dependent LRH-1 signaling pathways.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Suzanne G
authors.initials: SG
authors.lastname: Mays
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: C Denise
authors.initials: CD
authors.lastname: Okafor
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Micheal L
authors.initials: ML
authors.lastname: Tuntland
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Whitby
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Venkatasubramanian
authors.initials: V
authors.lastname: Dharmarajan
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Józef
authors.initials: J
authors.lastname: Stec
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.). eortlun@emory.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D003460:Crystallization; D006801:Humans; D056004:Molecular Dynamics Simulation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C082631:NR5A2 protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear