4WVD

Identification of a novel FXR ligand that regulates metabolism

「4II6」から置き換えられました

4WVD の概要

• エントリーDOI: 10.2210/pdb4wvd/pdb
• 分子名称: Nuclear receptor corepressor 1, Bile acid receptor, FORMIC ACID, ... (5 entities in total)
• 機能のキーワード: af-2 helix, ligand binding pocket, three-layer helical sandwich, transcription regulator fxr, bar, nr1h4, bile acid receptor, nhr, nuclear receptor, corepressor, transcription, transcription regulation
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus : O75376; Nucleus . Isoform 1: Nucleus . Isoform 2: Nucleus . Isoform 3: Nucleus . Isoform 4: Nucleus : Q96RI1
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 55059.29

構造登録者

Wang, R.,Li, Y. (登録日: 2014-11-05, 公開日: 2015-02-11, 最終更新日: 2025-03-12)

主引用文献

Jin, L.,Feng, X.,Rong, H.,Pan, Z.,Inaba, Y.,Qiu, L.,Zheng, W.,Lin, S.,Wang, R.,Wang, Z.,Wang, S.,Liu, H.,Li, S.,Xie, W.,Li, Y.
The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.
Nat Commun, 4:1937-, 2013

PubMed Abstract: Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.

PubMed: 23728580
DOI: 10.1038/ncomms2924

実験手法

X-RAY DIFFRACTION (2.9 Å)