6TFB

Carbamazepine binds Frizzled8

6TFB の概要

• エントリーDOI: 10.2210/pdb6tfb/pdb
• 分子名称: Frizzled-8, GLYCEROL, benzo[b][1]benzazepine-11-carboxamide, ... (4 entities in total)
• 機能のキーワード: wnt receptor frizzled8 carbamazepine, oncoprotein
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32378.98

構造登録者

Zhao, Y.,Jones, E.Y. (登録日: 2019-11-13, 公開日: 2020-02-26, 最終更新日: 2024-11-20)

主引用文献

Zhao, Y.,Ren, J.,Hillier, J.,Lu, W.,Jones, E.Y.
Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8.
J.Med.Chem., 63:3252-3260, 2020

PubMed Abstract: Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.

PubMed: 32049522
DOI: 10.1021/acs.jmedchem.9b02020

実験手法

X-RAY DIFFRACTION (1.68 Å)