6LXA
X-ray structure of human PPARalpha ligand binding domain-eicosapentaenoic acid (EPA) co-crystals obtained by delipidation and cross-seeding
Summary for 6LXA
| Entry DOI | 10.2210/pdb6lxa/pdb |
| Descriptor | Peroxisome proliferator-activated receptor alpha, GLYCEROL, 5,8,11,14,17-EICOSAPENTAENOIC ACID, ... (4 entities in total) |
| Functional Keywords | nuclear receptor, protein-ligand complex, ppar, transcription |
| Biological source | Homo sapiens |
| Total number of polymer chains | 1 |
| Total formula weight | 31250.60 |
| Authors | Kamata, S.,Saito, K.,Honda, A.,Ishikawa, R.,Oyama, T.,Ishii, I. (deposition date: 2020-02-10, release date: 2020-11-11, Last modification date: 2023-11-29) |
| 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 Cited by 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: 33205029DOI: 10.1016/j.isci.2020.101727 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.23 Å) |
Structure validation
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