Gani Osman A B S M, Sylte Ingebrigt
Department of Pharmacology, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, 9037 Tromsø, Norway.
Chem Biol Drug Des. 2008 Jul;72(1):50-7. doi: 10.1111/j.1747-0285.2008.00677.x. Epub 2008 Jun 11.
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.
过氧化物酶体增殖物激活受体γ属于核受体超家族，可被抗糖尿病药物罗格列酮和吡格列酮激活。过氧化物酶体增殖物激活受体γ的非配体依赖性组成型活性也得到了证实。X射线晶体学结构表明，受体的活性或非活性构象由C末端螺旋12的位置决定。在本研究中，使用分子动力学模拟来深入了解非活性和活性过氧化物酶体增殖物激活受体γ受体结构的激活过程和结构稳定性。模拟结果表明：（i）在活性位点没有激动剂的分子动力学模拟过程中，螺旋12处于与激活受体结构相对应位置的受体结构在结构上比螺旋12处于与非活性受体结构相对应位置的受体结构更稳定，这可能有助于受体的组成型活性；（ii）二十二碳六烯酸比格列酮类药物更有效地稳定活性受体构象；（iii）二十二碳六烯酸而非格列酮类药物诱导非活性受体结构发生结构变化，使螺旋12移动到更类似于活性受体结构的位置，这表明二十二碳六烯酸是一种比格列酮类药物更有效的过氧化物酶体增殖物激活受体γ激动剂。
