title: Phosphorylation of PPARγ Affects the Collective Motions of the PPARγ-RXRα-DNA Complex.
abstract: Peroxisome-proliferator activated receptor-γ (PPARγ) is a nuclear hormone receptor that forms a heterodimeric complex with retinoid X receptor-α (RXRα) to regulate transcription of genes involved in fatty acid storage and glucose metabolism. PPARγ is a target for pharmaceutical intervention in type 2 diabetes, and insight into interactions between PPARγ, RXRα, and DNA is of interest in understanding the function and regulation of this complex. Phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) has been shown to dysregulate the expression of metabolic regulation genes, an effect that is counteracted by PPARγ ligands. We applied molecular dynamics (MD) simulations to study the relationship between the ligand-binding domains of PPARγ and RXRα with their respective DNA-binding domains. Our results reveal that phosphorylation alters collective motions within the PPARγ-RXRα complex that affect the LBD-LBD dimerization interface and the AF-2 coactivator binding region of PPARγ.
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Lemkul
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, Virginia, United States of America; Nutritional Immunology & Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Lewis
authors.affiliation: Nutritional Immunology & Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
authors.affiliation: Department of Biochemistry, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Bevan
mesh_terms: D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D004247:DNA