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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Tara P. Azam & Luna Han & Erin E. Deans & Bin Huang & Reyal Hoxie & Larry J. Friedman & Jeff Gelles & Timothy O. Street, 2025. "Mechanism of client loading from BiP to Grp94 and its disruption by select inhibitors," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58658-w
    DOI: 10.1038/s41467-025-58658-w
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