Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them
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...
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Nature Portfolio
2025-05-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08189-3 |
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| author | Yan Zhong Li Shi Zhuo Xu Jing Gao Qingyu Ma Tianqi Gao Junying Tang Muya Xiong Yechun Xu Huixiong Dai Hu Zhou Naixia Zhang Chen Zhou |
| author_facet | Yan Zhong Li Shi Zhuo Xu Jing Gao Qingyu Ma Tianqi Gao Junying Tang Muya Xiong Yechun Xu Huixiong Dai Hu Zhou Naixia Zhang Chen Zhou |
| author_sort | Yan Zhong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-162917cf2ad14eb88fbe824ddc96d596 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-162917cf2ad14eb88fbe824ddc96d5962025-08-20T02:25:16ZengNature PortfolioCommunications Biology2399-36422025-05-018111710.1038/s42003-025-08189-3Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of themYan Zhong0Li Shi1Zhuo Xu2Jing Gao3Qingyu Ma4Tianqi Gao5Junying Tang6Muya Xiong7Yechun Xu8Huixiong Dai9Hu Zhou10Naixia Zhang11Chen Zhou12State Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesNational Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesUniversity of the Chinese Academy of SciencesUniversity of the Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesUniversity of the Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Chemical Biology, Analytical Research Center for Organic and Biological Molecules, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s42003-025-08189-3 |
| spellingShingle | Yan Zhong Li Shi Zhuo Xu Jing Gao Qingyu Ma Tianqi Gao Junying Tang Muya Xiong Yechun Xu Huixiong Dai Hu Zhou Naixia Zhang Chen Zhou Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them Communications Biology |
| title | Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them |
| title_full | Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them |
| title_fullStr | Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them |
| title_full_unstemmed | Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them |
| title_short | Benzbromarone interferes with the interaction between Hsp90 and Aha1 by interacting with both of them |
| title_sort | benzbromarone interferes with the interaction between hsp90 and aha1 by interacting with both of them |
| url | https://doi.org/10.1038/s42003-025-08189-3 |
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