The Amino-terminal Domain of Heat Shock Protein 90 (hsp90) That Binds Geldanamycin Is an ATP/ADP Switch Domain That Regulates hsp90 Conformation

TLDR

Heat shock protein 90 (hsp90) functions are inhibited by the drug geldanamycin, which binds specifically to the protein. The amino‑terminal domain of hsp90 harbors a shared geldanamycin‑binding site that also binds ATP/ADP; drug binding is exclusive to this domain, is inhibited by geldanamycin, and mutations in key glycine residues diminish both drug binding and ATP‑dependent conformational changes needed for co‑chaperone p23 association, indicating a common regulatory site.

Abstract

Many functions of the chaperone, heat shock protein 90 (hsp90), are inhibited by the drug geldanamycin that specifically binds hsp90. We have studied an amino-terminal domain of hsp90 whose crystal structure has recently been solved and determined to contain a geldanamycin-binding site. We demonstrate that, in solution, drug binding is exclusive to this domain. This domain also binds ATP linked to Sepharose through the γ-phosphate. Binding is specific for ATP and ADP and is inhibited by geldanamycin. Mutation of four glycine residues within two proposed ATP binding motifs diminishes both geldanamycin binding and the ATP-dependent conversion of hsp90 to a conformation capable of binding the co-chaperone p23. Since p23 binding requires regions outside the 1–221 domain of hsp90, these results indicate a common site for nucleotides and geldanamycin that regulates the conformation of other hsp90 domains.