8X9P

HURP (428-534)-alpha-tubulin-beta-tubulin complex

8X9P の概要

• エントリーDOI: 10.2210/pdb8x9p/pdb
• EMDBエントリー: 38178
• 分子名称: Tubulin alpha chain, Tubulin beta chain, Disks large-associated protein 5,Green fluorescent protein (3 entities in total)
• 機能のキーワード: hurp, tubulin, drug resistance, mitosis, cell cycle
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 172880.67

構造登録者

Chen, P.-P.,Hsia, K.-C. (登録日: 2023-11-30, 公開日: 2024-10-23, 最終更新日: 2025-07-02)

主引用文献

Saju, A.,Chen, P.P.,Weng, T.H.,Tsai, S.Y.,Tanaka, A.,Tseng, Y.T.,Chang, C.C.,Wang, C.H.,Shimamoto, Y.,Hsia, K.C.
HURP binding to the vinca domain of beta-tubulin accounts for cancer drug resistance.
Nat Commun, 15:8844-8844, 2024

PubMed Abstract: Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells' sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP's tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain's role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment.

PubMed: 39397030
DOI: 10.1038/s41467-024-53139-y

実験手法

ELECTRON MICROSCOPY (3.54 Å)