Mechanism of client loading from BiP to Grp94 and its disruption by select inhibitors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40234402.
- Also identified by DOI 10.1038/s41467-025-58658-w and PMC identifier 12000397.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- HSP90 Heat-Shock Proteins
- HSP70 Heat-Shock Proteins
- Heat-Shock Proteins
- Membrane Glycoproteins