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Ligand‐Induced Stabilization and Activation of Peroxisome Proliferator‐Activated Receptor γ
Author(s) -
Gani Osman A. B. S. M.,
Sylte Ingebrigt
Publication year - 2008
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2008.00677.x
Subject(s) - receptor , agonist , peroxisome proliferator activated receptor , chemistry , ligand (biochemistry) , enzyme linked receptor , nuclear receptor , peroxisome , peroxisome proliferator activated receptor alpha , biophysics , biochemistry , biology , transcription factor , gene
Peroxisome proliferator‐activated receptor γ 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 γ 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 γ 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 γ agonist than the glitazones.