Heat shock protein 90 as a molecular target for cancer therapeutics

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Heat shock protein 90 as a molecular target for cancer therapeutics Jennifer S Isaacs, Wanping Xu, Len Neckers Cancer Cell Volume 3, Issue 3, Pages 213-217 (March 2003) DOI: 10.1016/S1535-6108(03)00029-1

Figure 1 Nucleotide-dependent cycling of the Hsp90-based super-chaperone machine Hsp90 forms the basis of a super-chaperone machine that promotes the proper folding of client proteins so that they can respond to a stimulus or bind ligand. However, the machine is in constant flux and cycles between two Hsp90 conformations, determined by nucleotide binding, which in turn specify which set of cochaperones associate with the chaperone complex. Cochaperones that can associate with one conformation or the other include p23, p50Cdc37, p60Hop, immunophilins, cyclophilins, Hsp70, Hip, phosphatase PP5, Hsp40, and BAG-1. Cycling of this machine is driven by ATP hydrolysis. Although Hsp90 is a weak ATPase, its activity is regulated by cochaperones and dramatically enhanced by client protein binding. A client protein's half-life may be stochastically determined by the length of time it resides in association with the Hsp90-Hsp70 form of the chaperone machine, because at this time, the client protein is susceptible to ubiquitination and delivery to the proteasome. Cancer Cell 2003 3, 213-217DOI: (10.1016/S1535-6108(03)00029-1)

Figure 2 GA short-circuits the cycling of the Hsp90-based super-chaperone machine When GA or 17-AAG bind in Hsp90's nucleotide pocket, the drugs' high affinity for Hsp90 blocks the cycling of the chaperone machine and alters Hsp90's conformation to promote stable assembly of those components that favor client protein ubiquitination and proteasome delivery. Cancer Cell 2003 3, 213-217DOI: (10.1016/S1535-6108(03)00029-1)