4Y29

Identification of a novel PPARg ligand that regulates metabolism

Summary for 4Y29

• Entry DOI: 10.2210/pdb4y29/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, Peptide from Nuclear receptor coactivator 1, 1,2-dimethoxy-12-methyl[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium, ... (4 entities in total)
• Functional Keywords: af-2 helix, ligand binding pocket, three-layer helical sandwich, transcription regulator pparg, nr1c3, peroxisome proliferator-activated receptor gamma, nhr, nuclear receptor, coactivator, transcription factor, dna binding protein-transcription complex, dna binding protein/transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: P37231 Q15788
• Total number of polymer chains: 2
• Total formula weight: 32226.49

Authors

Wang, R.,Li, Y. (deposition date: 2015-02-09, release date: 2015-09-09, Last modification date: 2023-11-08)

Primary citation

Zheng, W.L.,Qiu, L.,Wang, R.,Feng, X.H.,Han, Y.P.,Zhu, Y.L.,Chen, D.Z.,Liu, Y.J.,Jin, L.H.,Li, Y.
Selective targeting of PPAR gamma by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency.
Sci Rep, 5:12222-12222, 2015

PubMed Abstract: Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPARγ, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPARγ but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPARγ binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPARγ. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice. Moreover, chelerythrine improved insulin sensitivity by more potently blocking the phosphorylation of PPARγ by CDK5 compared to TZDs. These data fundamentally elucidate the mechanism by which chelerythrine retains the benefits of improving insulin sensitivity while reducing the adverse effects of TZDs, suggesting that the natural product chelerythrine is a very promising pharmacological agent by selectively targeting PPARγ for further development in the clinical treatment of insulin resistance.

PubMed: 26183621
DOI: 10.1038/srep12222

Experimental method

X-RAY DIFFRACTION (1.98 Å)