3FUR

Crystal Structure of PPARg in complex with INT131

3FUR の概要

• エントリーDOI: 10.2210/pdb3fur/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, Nuclear receptor coactivator 1, 2,4-dichloro-N-[3,5-dichloro-4-(quinolin-3-yloxy)phenyl]benzenesulfonamide, ... (5 entities in total)
• 機能のキーワード: nuclear receptor, ppargamma, partial agonist, activator, alternative splicing, diabetes mellitus, disease mutation, dna-binding, metal-binding, nucleus, obesity, phosphoprotein, polymorphism, receptor, transcription, transcription regulation, zinc, zinc-finger, int131, transcription-transcription regulator complex, transcription/transcription regulator
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32987.36

構造登録者

Wang, Z.,Liu, J.,Walker, N. (登録日: 2009-01-14, 公開日: 2009-06-09, 最終更新日: 2024-03-20)

主引用文献

Motani, A.,Wang, Z.,Weiszmann, J.,McGee, L.R.,Lee, G.,Liu, Q.,Staunton, J.,Fang, Z.,Fuentes, H.,Lindstrom, M.,Liu, J.,Biermann, D.H.,Jaen, J.,Walker, N.P.,Learned, R.M.,Chen, J.L.,Li, Y.
INT131: a selective modulator of PPAR gamma.
J.Mol.Biol., 386:1301-1311, 2009

PubMed Abstract: The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR gamma; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPAR gamma that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPAR gamma. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPAR gamma target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPAR gamma responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemodynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPAR gamma through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but nonessential for INT131 function in vitro, providing one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes.

PubMed: 19452630
DOI: 10.1016/j.jmb.2009.01.025

実験手法

X-RAY DIFFRACTION (2.3 Å)