6L96

Structure of PPARalpha-LBD/pemafibrate/SRC1 peptide

Summary for 6L96

• Entry DOI: 10.2210/pdb6l96/pdb
• Descriptor: Peroxisome proliferator-activated receptor alpha, SRC1 coactivator peptide, (2~{R})-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid (3 entities in total)
• Functional Keywords: transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 64835.42

Authors

Kawasaki, M.,Kambe, A.,Yamamoto, Y.,Arulmozhira, S.,Ito, S.,Nakagawa, Y.,Tokiwa, H.,Nakano, S.,Shimano, H. (deposition date: 2019-11-08, release date: 2020-01-15, Last modification date: 2023-11-22)

Primary citation

Kawasaki, M.,Kambe, A.,Yamamoto, Y.,Arulmozhiraja, S.,Ito, S.,Nakagawa, Y.,Tokiwa, H.,Nakano, S.,Shimano, H.
Elucidation of Molecular Mechanism of a Selective PPAR alpha Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations.
Int J Mol Sci, 21:-, 2020

PubMed Abstract: The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα.

PubMed: 31935812
DOI: 10.3390/ijms21010361

Experimental method

X-RAY DIFFRACTION (3.2 Å)