title: Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism.
abstract: Ligand binding to proteins is not a static process, but rather involves a number of complex dynamic transitions. A flexible ligand can change conformation upon binding its target. The conformation and dynamics of a protein can change to facilitate ligand binding. The conformation of the ligand, however, is generally presumed to have one primary binding mode, shifting the protein conformational ensemble from one state to another. We report solution nuclear magnetic resonance (NMR) studies that reveal peroxisome proliferator-activated receptor γ (PPARγ) modulators can sample multiple binding modes manifesting in multiple receptor conformations in slow conformational exchange. Our NMR, hydrogen/deuterium exchange and docking studies reveal that ligand-induced receptor stabilization and binding mode occupancy correlate with the graded agonist response of the ligand. Our results suggest that ligand and receptor dynamics affect the graded transcriptional output of PPARγ modulators.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Travis S
authors.initials: TS
authors.lastname: Hughes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chalmers
authors.forename: Scott
authors.initials: S
authors.lastname: Novick
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Mark
authors.initials: M
authors.lastname: Rance
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
mesh_terms: D041961:Deuterium Exchange Measurement; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D047495:PPAR gamma / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D000077154:Rosiglitazone; D045162:Thiazolidinediones
chemical_list: D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone