![]() After the first hydrolysis step, the Hsp90 dimer was suggested to undergo a flip into a closed asymmetric state, followed by a second hydrolysis event. 11 further showed that ATP hydrolysis in the two protomers is sequential and deterministic in the mitochondrial Hsp90, TRAP1, with different hydrolysis rates for each protomer. The thermodynamic driving force for this global conformational change originates from the tightly coupled slow ATPase reaction on ~0.1–1 min −1 timescales 10. ATP-binding triggers large conformational changes in the global Hsp90 structure, stabilizing the compact closed conformation of the enzyme 9. The ATP-binding site of Hsp90 is located in the NTD, and it is completed by residues from the M-domain, including an arginine (Arg-380 in yeast Hsp90) that forms contacts with the γ-phosphate of ATP 9. The closing exposes important client-binding regions, as shown in recent cryo-EM structures of Hsp90 in complex with co-chaperones and clients 7, 8. During its chaperone cycle, Hsp90 undergoes large-scale conformational changes from an open inactive state to a closed active state, which induce association of the M-domains and NTDs 5, 6. This 90 kDa, highly conserved, homodimeric enzyme comprises an N-terminal domain (NTD), a middle domain (M-domain), and a C-terminal domain (CTD) (Fig. Stringent clients of Hsp90 include 60% of the human kinome and the chaperone is therefore of significant biomedical interest. The heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that controls protein maturation and folding, in addition to central regulatory functions of the eukaryotic cell 1, 2, 3.
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