8Z3H

Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them

Summary for 8Z3H

• Entry DOI: 10.2210/pdb8z3h/pdb
• Descriptor: Activator of 90 kDa heat shock protein ATPase homolog 1 (2 entities in total)
• Functional Keywords: holdase, activator of hsp90, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15185.16

Authors

Shi, L.,Zhong, Y.,Tang, J.,Xu, Z.,Zhang, N. (deposition date: 2024-04-15, release date: 2025-04-23, Last modification date: 2025-11-05)

Primary citation

Zhong, Y.,Shi, L.,Xu, Z.,Gao, J.,Ma, Q.,Gao, T.,Tang, J.,Xiong, M.,Xu, Y.,Dai, H.,Zhou, H.,Zhang, N.,Zhou, C.
Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them.
Commun Biol, 8:761-761, 2025

PubMed Abstract: Aha1 is one of the well-known co-chaperones of Hsp90. However, the action mode of Aha1 has not been fully elucidated yet, and the binding mode of Aha1's C-terminal domain (Aha1-CTD) to Hsp90 is still under discussion. Meanwhile, since both Hsp90 and Aha1 contribute to tumorigenesis through controlling the homeostasis of onco-proteins, Hsp90-Aha1 system might serve as a target for anti-tumor drug development. A few of active compounds towards Hsp90-Aha1 system have been reported during the past years, but no compound binding pocket in Aha1 was pictured yet. Here in this manuscript, by using the discovered dual-modulator Benzbromarone as the probe, the pocket in Aha1 responsible for compound recognition is defined. Interestingly, as shown by the cryo-EM structures of Hsp90:Aha1 system, it is the same pocket that is involved in the in vitro interaction between Aha1-CTD and Hsp90-MD. Besides, Benzbromarone's binding to Hsp90-NTD also exhibits unique structural features. Not surprisingly, due to the interference with the Hsp90 machinery, Benzbromarone could down-regulate the ATPase activity of the chaperone. Finally, according to the cellular-based experimental data, Benzbromarone has been shown to exhibit cytotoxicity against multiple cancer cell types, at least in part, through its modulation of the Hsp90 system.

PubMed: 40379881
DOI: 10.1038/s42003-025-08189-3

Experimental method

X-RAY DIFFRACTION (1.5 Å)