HSP90 is a fundamental chaperone protein for many cellular processes. Through its involvement in the folding of many oncoproteins, it is a therapeutic target against cancer. HSP90 is affected by complex structural rearrangements associated with ATP binding and hydrolysis during its functional cycle. However, these structural rearrangements remain poorly described for the apo protein.
In this study, researchers from IBS and ILM-Lyon have, for the first time, identified a metastable excited state of the HSP90 domain containing the ATP binding site, by integrating NMR and molecular dynamics. Directed mutagenesis allowed to resolve the structures of both the ground state and the excited state of this protein. The NMR dynamics study allowed to characterize the kinetics and thermodynamics of the interconversion between these two states. This study demonstrates that a functional state of HSP90 with the ATP-lid in the closed position, more than 30 Å away from its position in the ground state, is already populated in solution and in the absence of ATP.
The description of the structures sampled by HSP90 and their dynamics provides valuable information for the design of future therapeutic ligands
Visualizing the transiently populated closed-state of human HSP90 ATP binding domain. Henot F, Rioual E, Favier A, Macek P, Crublet E, Josso P, Brutscher B, Frech M, Gans P, Loison C, Boisbouvier J. Nature Communications 2022;13(1):7601. doi: 10.1038/s41467-022-35399-8
Contact IBS : Jérôme Boisbouvier (IBS/Biomolecular NMR Spectroscopy Group))