Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Targeting the dynamic HSP90 complex in cancer. The Hsp90 molecular chaperone: an open and shut case for treatment. Emerging picture of host chaperone and cyclophilin roles in RNA virus replication. Nagy, P.D., Wang, R.Y., Pogany, J., Hafren, A. Chaperone machines for protein folding, unfolding and disaggregation. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. The activating co-chaperone Aha1 mobilized the lid of apo Hsp90, suggesting an early role in the catalytic cycle. We identified a two-step mechanism for lid closure over the nucleotide-binding pocket. Nanosecond single-molecule fluorescence fluctuation analysis uncovered that critical structural elements that undergo rearrangement were mobile on a sub-millisecond time scale. We found that the ATPase activity of the chaperone was reflected in the kinetics of specific structural rearrangements at remote positions that acted cooperatively. Here we engineered one-nanometer fluorescence probes based on photoinduced electron transfer into the yeast Hsp90 to observe these motions. Crystallographic studies have defined distinct conformational states of the mechanistic core, implying structural changes that have not yet been observed in solution. Hsp90 functions as a molecular clamp that closes and opens in response to the binding and hydrolysis of ATP. The Hsp90 chaperone is a central node of protein homeostasis, activating many diverse client proteins.
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