title: Characterization of covalent bond formation between PPARγ and oxo-fatty acids.
abstract: Covalent modification of proteins is important for normal cellular regulation. Here, we report on the covalent modification of peroxisome proliferator-activated receptor γ (PPARγ), an important drug target, by oxo-fatty acids. In this study, ESI mass spectroscopy showed that the reactivities of oxo-fatty acids with PPARγ are different from one another and that these behaviors are related to the structure of the fatty acids. X-ray crystallography showed that three oxo-fatty acids all bound to the same residue of PPARγ (Cys285), but displayed different hydrogen bonding modes. Moreover, fatty acids formed covalent bonds with both PPARγ moieties in the homodimer, one in an active conformation and the other in an alternative conformation. These two conformations may explain why covalently bound fatty acids show partial rather than full agonist activity.
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Egawa
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004281:Docosahexaenoic Acids / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D047495:PPAR gamma / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021241:Spectrometry, Mass, Electrospray Ionization; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D008024:Ligands; D047495:PPAR gamma; D020033:Protein Isoforms; D004281:Docosahexaenoic Acids