Determination of the critical amino acids involved in the peroxisome proliferator-activated receptor (PPAR) δ selectivity of phenylpropanoic acid-derived agonists

Jun Ichi Kasuga, Takuji Oyama, Izumi Nakagome, Makoto Makishima, Shuichi Hirono, Kosuke Morikawa, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Phenylpropanoic acid-derived PPAR agonist TIPP-204, shows high selectivity for human (h)PPARδ while structurally related TIPP-401 is a hPPARα/δ dual agonist. Computational docking of TIPP-401 in the ligand binding domain (LBD) of hPPARα and hPPARδ, and inspection of the TIPP-204-hPPARδ LBD co-crystal structure identified key amino acids responsible for the differences in selectivity of the two analogues. These results were confirmed using mutagenesis assays. The amino acids determining the potency and selectivity of TIPP-204 are different to those of the PPARδ-selective agonist GW-501516, which belongs to a different chemical class. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)1662-1666
Number of pages5
JournalChemMedChem
Volume3
Issue number11
DOIs
Publication statusPublished - Nov 17 2008

Keywords

  • Mutagenesis
  • PPARδ-selective agonists
  • Protein structures
  • Receptors
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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