Fig. 1.

Structure and mechanism of heat shock protein 90 (HSP90). (A) Structure domains of the HSP90 protein. N-temminal domain (NTD) is the N-terminal domain which binds adenosine triphosphate (ATP), HSP90 inhibitors such as geldanamycin, and co-chaperones such as Cdc37. Middle domain (MD) is short for the middle domain that contains a catalytic arginine required for the adenosine triphosphatase (ATPase) activity. C-terminal domain (CTD) is the C-terminal domain which contains the major dimerization interface. While all three domains are involved in client protein binding, MD is the major protein binding site. (B) The ATP cycling working mode proposed for the HSP90 machinery. The HSP90 machinery transits from the "open" to the "ATP-binding" state on ATP binding; then the NTD region closes over the ATP-bound active site to enter the "closed" state that is rate-limiting. After ATP hydrolysis, inorganic phosphate (Pi) is released and the HSP90 machinery enters the "adenosine diphosphate (ADP)-binding" state. The two NTDs then dissociate to allow subsequent release of ADP and the return of HSP90 back to the "open" conformation.