Structural comparison of inhibitor binding to Hsp90 isoforms.

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Hsp90α, Hsp90β, Grp94 and TRAP1 are a family of cellular chaperone proteins responsible for maturation of a variety of key client proteins involved in cell growth. The last step in the refolding process is ATP-dependent and ATPase activity is required for the operation of a functional ’chaperone’ cycle which leads to stabilisation of oncogenic client proteins such as ErbB2, Raf-1 and CDK4. The N-terminal domain of Hsp90s (Nt-Hsp90) contain an unusually shaped ATP binding cleft that can be inhibited with some selectivity by ansamycin antibiotics such as geldanamycin. Recent studies with geldanamycin derivatives such as 17-AAG suggest that cancer cells are particularly sensitive to Hsp90 inhibition, with the degradation of mis-folded client proteins inducing apoptosis and subsequent tumour cytostatis. These results suggest the Hsp90 family may be an appropriate target for anti-cancer drug development. We have determined the structure of the N terminal domain of Hsp90α, Hsp90β and Grp94 in complex with a number of ligands that bind to the ATP binding site. Although the structures of Hsp90α and Hsp90β are essentially identical, there is some variation in the details of the active site of Grp94 in response to different ligands. These changes could provide an opportunity for structure-based design of selective ligands that could be valuable in probing the differential biology of these Hsp90 isoforms.