Molecular modelling of the peroxisome proliferator-activated receptor alpha (PPAR alpha) from human, rat and mouse, based on homology with the human PPAR gamma crystal structure.
The generation of homology models of human, rat and mouse peroxisome proliferator-activated receptor alpha (PPAR alpha) are reported, based on the recently published crystal structure of the human PPAR gamma ligand-binding domain (LBD) with bound ligand, rosiglitazone. It is found that a template of peroxisome proliferating fibrate drugs and related compounds can fit within the putative ligand-binding site of rat PPAR alpha, via contacts with amino acid residues which are consistent with their biological potency for peroxisome proliferation, site-directed mutagenesis experiments and with quantitative structure-activity relationship (QSAR) analysis studies. The experimental binding affinity of leukotriene B(4) (LTB(4)) for the mouse PPAR alpha agrees closely with the calculated value based on the modelled interactions, whereas selective PPAR alpha ligands such as clofibric acid are able to fit the human PPAR alpha binding site in agreement with reported site-directed mutagenesis information.
Lewis
D F V
DF
School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. d.lewis@surrey.ac.uk
Jacobs
M N
MN
Dickins
M
M
Lake
B G
BG
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D006168:Guinea Pigs; D006801:Humans; D007975:Leukotriene B4 / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020025:Peroxisome Proliferators / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014157:Transcription Factors / Q000737:chemistry* / Q000145:classification / Q000378:metabolism
D008024:Ligands; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D007975:Leukotriene B4