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. 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.