Ligand-induced stabilization and activation of peroxisome proliferator-activated receptor gamma.
Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end. In this study, molecular dynamics simulations were used to gain molecular insight into the activation process and the structural stability of inactive and active peroxisome proliferator-activated receptor gamma receptor structure. The simulations showed: (i) during molecular dynamics simulations without agonist at the active site, the receptor structure with helix 12 in a position corresponding to activated receptor structure was structurally more stable than with helix 12 in a position corresponding to inactive receptor structure, which may contribute to the constitutive activity of the receptor; (ii) docosahexenoic acid stabilized the active receptor conformation more efficiently than the glitazones; (iii) docosahexenoic acid, but not glitazones, induced structural changes into the inactive receptor structure such that helix 12 was shifted into a position more similar to that of an active receptor structure, which indicate that docosahexenoic acid is a more effective peroxisome proliferator-activated receptor gamma agonist than the glitazones.
Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway.
Osman A B S M
OA
Gani
Ingebrigt
I
Sylte
D001665:Binding Sites; D003198:Computer Simulation; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation; D004795:Enzyme Stability; D007004:Hypoglycemic Agents / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry*; D011487:Protein Conformation; D045162:Thiazolidinediones / Q000737:chemistry
D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D004281:Docosahexaenoic Acids