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Mechanistic elucidation guided by covalent inhibitors for the development of anti-diabetic PPAR gamma ligands
- Title
- Mechanistic elucidation guided by covalent inhibitors for the development of anti-diabetic PPAR gamma ligands
- Authors
- Bae, Hwan; Jang, Jun Young; Choi, Sun-Sil; Lee, Jae-Jin; Kim, Heejun; Jo, Ala; Lee, Kong-Joo; Choi, Jang Hyun; Suh, Se Won; Park, Seung Bum
- Ewha Authors
- 이공주; 이제진
- SCOPUS Author ID
- 이공주; 이제진
- Issue Date
- 2016
- Journal Title
- CHEMICAL SCIENCE
- ISSN
- 2041-6520
2041-6539
- Citation
- CHEMICAL SCIENCE vol. 7, no. 8, pp. 5523 - 5529
- Publisher
- ROYAL SOC CHEMISTRY
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-regulated transcription factor that plays crucial roles in adipogenesis, lipid metabolism, and glucose homeostasis. Several PPAR gamma ligands possess anti-diabetic activity and they commonly inhibit the phosphorylation of PPAR gamma at serine 273 (Ser273). The recently reported PPAR gamma ligand SR1664, which selectively blocks the phosphorylation of PPARg without classical agonism, has potent anti-diabetic activity, indicating that the inhibition of Ser273 phosphorylation is sufficient to provoke anti-diabetic effects. In this study, we revealed the X-ray structure of PPAR gamma co-crystallized with SR1664 bound to the alternate binding site of PPAR gamma and confirmed that the alternate site binding of SR1664 blocks the phosphorylation of Ser273. Furthermore, using covalent inhibitors as chemical tools, we demonstrated that the inhibition of phosphorylation is attributed to the occupation of a specific site which is a hydrophobic region between helix 3 and beta 3-beta 4 at the binding pocket of PPAR gamma. In high-fat diet-induced obese mice, we confirmed the anti-diabetic activity of our covalent inhibitor SB1453 that was designed to bind at the specific site in PPAR gamma for blocking the phosphorylation of Ser273. Lastly, the target selectivity of SB1453 was demonstrated by fluorescence-based visualization of target proteins complexed with the covalent probe 11 containing a bioorthogonal functional group.
- DOI
- 10.1039/c6sc01279e
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
- Files in This Item:
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