6KXX
Human PPAR alpha ligand binding domain in complex with a synthetic agonist (compound A)
Summary for 6KXX
| Entry DOI | 10.2210/pdb6kxx/pdb |
| Descriptor | Peroxisome proliferator-activated receptor alpha, PGC1alpha, 1-(4-chlorophenyl)-6-methyl-3-propan-2-yl-pyrazolo[3,4-b]pyridine-4-carboxylic acid, ... (4 entities in total) |
| Functional Keywords | agonist, complex, nuclear receptor, transcription |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 33420.38 |
| Authors | Yoshida, T.,Tachibana, K.,Oki, H.,Doi, M.,Fukuda, S.,Yuzuriha, T.,Tabata, R.,Ishimoto, K.,Kawahara, K.,Ohkubo, T.,Miyachi, H.,Doi, T. (deposition date: 2019-09-14, release date: 2020-05-20, Last modification date: 2024-03-27) |
| Primary citation | Yoshida, T.,Oki, H.,Doi, M.,Fukuda, S.,Yuzuriha, T.,Tabata, R.,Ishimoto, K.,Kawahara, K.,Ohkubo, T.,Miyachi, H.,Doi, T.,Tachibana, K. Structural Basis for PPAR alpha Activation by 1H-pyrazolo-[3,4-b]pyridine Derivatives. Sci Rep, 10:7623-7623, 2020 Cited by PubMed Abstract: Small-molecule agonism of peroxisome proliferator-activated receptor α (PPARα), a ligand-activated transcriptional factor involved in regulating fatty acid metabolism, is an important approach for treating dyslipidemia. Here, we determined the structures of the ligand-binding domain (LBD) of PPARα in complex with 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives, which were recently identified as PPARα-selective activators with markedly different structures from those of the well-known PPARα agonists fibrates. The crystal structures of the complexes showed that they form a canonical hydrogen-bond network involving helix 12 in the LBD, which is thought to be essential for PPARα activation, as also observed for fibrates. However, the phenyl side chain of the compounds occupies a small cavity between Ile272 and Ile354, which is rarely accessed by fibrates. This unique feature may be essential for subtype selectivity and combine with the well-characterized binding mode of fibrates to improve activity. These findings demonstrate the advantage of using 1H-pyrazolo-[3,4-b]pyridine as a skeleton of PPARα agonists and provide insight into the design of molecules for treating dyslipidemia. PubMed: 32376995DOI: 10.1038/s41598-020-64527-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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