3GBK

Crystal Structure of Human PPAR-gamma Ligand Binding Domain Complexed with a Potent and Selective Agonist

Summary for 3GBK

• Entry DOI: 10.2210/pdb3gbk/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2-[(1-{3-[4-(biphenyl-4-ylcarbonyl)-2-propylphenoxy]propyl}-1,2,3,4-tetrahydroquinolin-5-yl)oxy]-2-methylpropanoic acid (3 entities in total)
• Functional Keywords: ppar aganists, x-ray co-crystal analysis, structure-based drug design, selective, type ii diabetes, activator, alternative splicing, diabetes mellitus, disease mutation, dna-binding, metal-binding, nucleus, obesity, phosphoprotein, polymorphism, receptor, transcription, transcription regulation, zinc, zinc-finger, ligand binding protein
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 62585.78

Authors

Peng, Y.-H.,Lin, C.-H.,Hsieh, H.-P.,Wu, S.-Y. (deposition date: 2009-02-19, release date: 2009-12-29, Last modification date: 2023-11-01)

Primary citation

Lin, C.-H.,Peng, Y.-H.,Coumar, M.S.,Chittimalla, S.K.,Liao, C.-C.,Lyn, P.-C.,Huang, C.-C.,Lien, T.-W.,Lin, W.-H.,Hsu, J.T.-A.,Cheng, J.-H.,Chen, X.,Wu, J.-S.,Chao, Y.-S.,Lee, H.-J.,Juo, C.-G.,Wu, S.-Y.,Hsieh, H.-P.
Design and structural analysis of novel pharmacophores for potent and selective peroxisome proliferator-activated receptor gamma agonists
J.Med.Chem., 52:2618-2622, 2009

PubMed Abstract: Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.

PubMed: 19301897
DOI: 10.1021/jm801594x

Experimental method

X-RAY DIFFRACTION (2.3 Å)