Mechanism of client loading from BiP to Grp94 and its disruption by select inhibitors

Tara P. Azam, Luna Han, Erin E. Deans, Bin Huang, Reyal Hoxie, Larry J. Friedman, Jeff Gelles and Timothy O. Street ()
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Tara P. Azam: Department of Biochemistry at Brandeis University
Luna Han: Department of Biochemistry at Brandeis University
Erin E. Deans: Department of Biochemistry at Brandeis University
Bin Huang: Department of Biochemistry at Brandeis University
Reyal Hoxie: Department of Biochemistry at Brandeis University
Larry J. Friedman: Department of Biochemistry at Brandeis University
Jeff Gelles: Department of Biochemistry at Brandeis University
Timothy O. Street: Department of Biochemistry at Brandeis University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Hsp90 chaperones are a long-standing cancer drug target with numerous ATP-competitive inhibitors in clinical trials. Client proteins are transferred from Hsp70 to Hsp90 in a stepwise process of client delivery, loading, and trapping, but little is known about how inhibitors influence these steps. By examining the ER-resident BiP/Grp94 system (Hsp70/Hsp90 paralogs), we discover that some inhibitors allow BiP to push Grp94 into the client loading conformation, whereas other inhibitors block this conformational change and destabilize a BiP/client/Grp94 ternary complex. We uncover how BiP drives Grp94 into the client loading state and identify a structural explanation for why only a select group of inhibitors disrupt client loading on Grp94. These results show a client loading mechanism with specific shared features between the Hsp70/Hsp90 systems in the ER and cytosol and open a new avenue for rational Hsp90 drug design.

Date: 2025
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DOI: 10.1038/s41467-025-58658-w

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