6KB9

X-ray structure of human PPARalpha ligand binding domain-pemafibrate co-crystals obtained by cross-seeding

Summary for 6KB9

• Entry DOI: 10.2210/pdb6kb9/pdb
• Descriptor: Peroxisome proliferator-activated receptor alpha, GLYCEROL, (2~{R})-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid, ... (4 entities in total)
• Functional Keywords: nuclear receptor, protein-ligand complex, ppar, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31438.69

Authors

Kamata, S.,Saito, K.,Honda, A.,Ishikawa, R.,Oyama, T.,Ishii, I. (deposition date: 2019-06-24, release date: 2020-11-11, Last modification date: 2023-11-22)

Primary citation

Kamata, S.,Oyama, T.,Saito, K.,Honda, A.,Yamamoto, Y.,Suda, K.,Ishikawa, R.,Itoh, T.,Watanabe, Y.,Shibata, T.,Uchida, K.,Suematsu, M.,Ishii, I.
PPAR alpha Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.
Iscience, 23:101727-101727, 2020

PubMed Abstract: Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARα ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARα agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.

PubMed: 33205029
DOI: 10.1016/j.isci.2020.101727

Experimental method

X-RAY DIFFRACTION (1.55 Å)