7VUE

Structural insight of the molecular mechanism of cilofexor bound to FXR

7VUE の概要

• エントリーDOI: 10.2210/pdb7vue/pdb
• 分子名称: Bile acid receptor, Peptide from Nuclear receptor coactivator 2, 2-[3-[4-[[3-[2,6-bis(chloranyl)phenyl]-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-chloranyl-phenyl]-3-oxidanyl-azetidin-1-yl]pyridine-4-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: nuclear receptor, ligand binding, nuclear protein
• 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: 28742.19

構造登録者

Jiang, L.,Chen, Y.C. (登録日: 2021-11-02, 公開日: 2022-03-16, 最終更新日: 2024-11-06)

主引用文献

Jiang, L.,Liu, X.,Wei, H.,Dai, S.,Qu, L.,Chen, X.,Guo, M.,Chen, Y.
Structural insight into the molecular mechanism of cilofexor binding to the farnesoid X receptor.
Biochem.Biophys.Res.Commun., 595:1-6, 2022

PubMed Abstract: Farnesoid X receptor (FXR) is a bile acid-related nuclear receptor and is considered a promising target to treat several liver disorders. Cilofexor is a selective FXR agonist and has already entered phase III trials in primary sclerosing cholangitis (PSC) patients. Pruritis caused by cilofexor treatment is dose dependent. The binding characteristics of cilofexor with FXR and its pruritogenic mechanism remain unclear. In our research, the affinity of cilofexor bound to FXR was detected using an isothermal titration calorimetry (ITC) assay. The binding mechanism between cilofexor and FXR-LBD is explained by the cocrystal structure of the FXR/cilofexor complex. Structural models indicate the possibility that cilofexor activates Mas-related G protein-coupled receptor X4 (MRGPRX4) or G protein-coupled bile acid receptor 1 (GPBAR1), leading to pruritus. In summary, our analyses provide a molecular mechanism of cilofexor binding to FXR and provide a possible explanation for the dose-dependent pruritis of cilofexor.

PubMed: 35091108
DOI: 10.1016/j.bbrc.2022.01.069

実験手法

X-RAY DIFFRACTION (2.601 Å)