Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations

Masao Ohashi, Kanae Gamo, Takuji Oyama, Hiroyuki Miyachi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180°away from that of bound 2. These results support our previous proposal that the hPPARγ LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

Original languageEnglish
Pages (from-to)2758-2762
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number14
DOIs
Publication statusPublished - Jun 4 2015

Keywords

  • PPAR
  • Partial agonist
  • Peroxisome proliferator-activated receptor
  • X-ray

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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