8X9P

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

Summary for 8X9P

• Entry DOI: 10.2210/pdb8x9p/pdb
• EMDB information: 38178
• Descriptor: Tubulin alpha chain, Tubulin beta chain, Disks large-associated protein 5,Green fluorescent protein (3 entities in total)
• Functional Keywords: hurp, tubulin, drug resistance, mitosis, cell cycle
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 3
• Total formula weight: 172880.67

Authors

Chen, P.-P.,Hsia, K.-C. (deposition date: 2023-11-30, release date: 2024-10-23, Last modification date: 2025-05-14)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.54 Å)