4EMA

Human peroxisome proliferator-activated receptor gamma in complex with rosiglitazone

Summary for 4EMA

• Entry DOI: 10.2210/pdb4ema/pdb
• Related: 1PRG 1ZEO 2VV1 3DZU 3DZY 3GWX 4EM9
• Descriptor: Peroxisome proliferator-activated receptor gamma, 2,4-THIAZOLIDIINEDIONE, 5-[[4-[2-(METHYL-2-PYRIDINYLAMINO)ETHOXY]PHENYL]METHYL]-(9CL) (3 entities in total)
• Functional Keywords: nuclear receptor, retinoic acid receptor, nucleus, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P37231
• Total number of polymer chains: 2
• Total formula weight: 63178.40

Authors

Liberato, M.V.,Nascimento, A.S.,Polikarpov, I. (deposition date: 2012-04-11, release date: 2013-03-06, Last modification date: 2024-02-28)

Primary citation

Liberato, M.V.,Nascimento, A.S.,Ayers, S.D.,Lin, J.Z.,Cvoro, A.,Silveira, R.L.,Martinez, L.,Souza, P.C.,Saidemberg, D.,Deng, T.,Amato, A.A.,Togashi, M.,Hsueh, W.A.,Phillips, K.,Palma, M.S.,Neves, F.A.,Skaf, M.S.,Webb, P.,Polikarpov, I.
Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) Gamma activators and pan-PPAR partial agonists
Plos One, 7:e36297-e36297, 2012

PubMed Abstract: Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

PubMed: 22649490
DOI: 10.1371/journal.pone.0036297

Experimental method

X-RAY DIFFRACTION (2.545 Å)