6KXY

Human PPAR alpha ligand binding domain in complex with a synthetic agonist (compound B)

6KXY の概要

• エントリーDOI: 10.2210/pdb6kxy/pdb
• 分子名称: Peroxisome proliferator-activated receptor alpha, PGC1alpha, 6-ethyl-1-(4-fluorophenyl)-3-pentan-3-yl-pyrazolo[3,4-b]pyridine-4-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: agonist, complex, nuclear receptor, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 33446.00

構造登録者

Yoshida, T.,Tachibana, K.,Oki, H.,Doi, M.,Fukuda, S.,Yuzuriha, T.,Tabata, R.,Ishimoto, K.,Kawahara, K.,Ohkubo, T.,Miyachi, H.,Doi, T. (登録日: 2019-09-14, 公開日: 2020-05-20, 最終更新日: 2023-11-22)

主引用文献

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

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: 32376995
DOI: 10.1038/s41598-020-64527-x

実験手法

X-RAY DIFFRACTION (2 Å)