title: Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta) selective ligand binding.
abstract: Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.
authors.affiliation: Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, Sao Paulo, Brazil.
authors.forename: Fernanda A H
authors.initials: FA
authors.lastname: Batista
authors.forename: Daniela B B
authors.initials: DB
authors.lastname: Trivella
authors.forename: Amanda
authors.initials: A
authors.lastname: Bernardes
authors.forename: Joyce
authors.initials: J
authors.lastname: Gratieri
authors.forename: Paulo S L
authors.initials: PS
authors.lastname: Oliveira
authors.forename: Ana Carolina M
authors.initials: AC
authors.lastname: Figueira
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Igor
authors.initials: I
authors.lastname: Polikarpov
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D047493:PPAR alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D008024:Ligands; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D011994:Recombinant Proteins; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds