Interaction of some peroxisome proliferators with the mouse liver peroxisome proliferator-activated receptor (PPAR): a molecular modelling and quantitative structure-activity relationship (QSAR) study
- 1 January 1993
- journal article
- research article
- Published by Taylor & Francis in Xenobiotica
- Vol. 23 (1) , 79-96
- https://doi.org/10.3109/00498259309059364
Abstract
1. The three-dimensional structure of a portion of the ligand-binding domain of the mouse liver peroxisome proliferator-activated receptor (PPAR) described by Issemann and Green (1990) has been modelled from amino acid sequence data. 2. By inspection of the three-dimensional structure of the portion of the PPAR ligand-binding domain, a putative binding site for peroxisome proliferators, consisting of one isoleucine, one lysine and two phenylalanine moieties (residues 354, 358, 359 and 361, respectively), has been identified. 3. The interaction of 12 peroxisome proliferators with the putative PPAR binding site has been investigated and energetics of binding calculated from ligand-bound and ligand-free receptor geometries. 4. The interaction data have been used to establish quantitative structure-activity relationships (QSARs) between peroxisome proliferator binding and either PPAR activation in COS1 cells or induction of palmitoyl-CoA oxidation in rat hepatocyte cultures. 5. The results are discussed in terms of the role of PPAR in the mechanism of initiation of peroxisome proliferation in rodent liver.Keywords
This publication has 41 references indexed in Scilit:
- Peroxisome proliferation and nongenotoxic carcinogenesis: Commentary on a symposium*1Fundamental and Applied Toxicology, 1991
- Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferatorsNature, 1990
- Hydrophobic cluster analysis (HCA) of the hormone-binding domain of receptor proteinsJournal of Steroid Biochemistry, 1989
- Inhibition of hepatic fatty acid oxidation by bezafibrate and bezafibroyl CoABiochemical and Biophysical Research Communications, 1988
- Structure-Activity Relationships for Induction of Peroxisomal Enzyme Activities By Phthalate Monoesters in Primary Rat Hepatocyte CulturesToxicology and Industrial Health, 1987
- Possible steroid binding site common to adrenal cytochrome P-450scc and prostatic steroid binding proteinFEBS Letters, 1985
- Action of clofibrate and its analogs in rats dissociation of hypolipidemic effects and the induction of peroxisomal β-oxidationBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1984
- Clobuzarit: Species differences in the morphological and biochemical response of the liver following chronic administrationToxicology and Applied Pharmacology, 1984
- Detection of a nafenopin-binding protein in rat liver cytosol associated with the induction of peroxisome proliferation by hypolipidemic compoundsBiochemical and Biophysical Research Communications, 1983
- Review of the hepatic response to hypolipidaemic drugs in rodents and assessment of its toxicological significance to manFood and Cosmetics Toxicology, 1981