Year: 2025
Type: article
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.
Source: Nature Communications
Authors: Tara P. Azam, Jiaqi Han, Erin E. Deans, Bin Huang, Reyal Hoxie, Larry J. Friedman, Jeff Gelles, Timothy O. Street
Institution: Brandeis University
Language: English
Topic: Heat shock proteins research
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1133315554, G1943965328, G2221420653, G2289024685, G2664165150, G2828608490, G5561599632, Single-molecule visualization of transcription regulation mechanisms, Joint Bayesian analysis of single-molecule colocalization images and kinetics, G7331139308, G7871215676, G834884231, Mechanism by which the Grp94 molecular chaperone folds insulin-like growth factors, G9000022036, G9000197315, G9000269296, G9000285443
OpenAlex ID: W4409480228