Atomic structure of mutant PPARγ LBD complexed with 15d-PGJ₂: Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands

Abstract 

15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) activates a nuclear receptor heterodimer, peroxisome proliferators-activated receptor γ (PPARγ)/ retinoid X receptor (RXRα) through covalent binding to Cys285 in PPARγ ligand-binding domain (LBD). Here, we present the 1.9Å crystal structure of C285S mutant LBD complexed with 15d-PGJ₂, corresponding to the non-covalently bound state. The ligand lies adjacent to a hydrogen-bond network around the helix H2 and the nearby β-sheet. Comparisons with previous structures clarified the relationships between PPARγ function and conformational alterations of LBD during the process of covalently binding ligands, such as 15d-PGJ₂, and thus suggested a mechanism, by which these ligands modulate PPARγ/RXRα function through conformational changes of the loop following helix H2′ and the β-sheet.

Abbreviations: PPARγ, peroxisome proliferators-activated receptor γ, RXR, retinoid X receptor, 15d-PGJ₂, 15-deoxy-Δ^12,14-prostaglandin J₂, LBD, ligand-binding domain, LBP, ligand-binding pocket, DBD, DNA-binding domain

Keywords: PPARγ, covalently bound ligand, PPARγ/RXRα, activating process, modulation mechanism, Crystal structure