THE AMINO-TERMINAL DOMAIN OF HEAT-SHOCK-PROTEIN-90 (HSP90) THAT BINDSGELDANAMYCIN IS AN ATP ADP SWITCH DOMAIN THAT REGULATES HSP90 CONFORMATION/

Many functions of the chaperone, heat shock protein 90 (hsp90), are in hibited by the drug geldanamycin that specifically binds hsp90, We hav e studied an amino-terminal domain of hsp90 whose crystal structure ha s recently been solved and determined to contain a geldanamycin bindin g site. We demonstrate that, in solution, drug binding is exclusive to this domain. This domain also binds ATP linked to Sepharose through t he gamma-phosphate. Binding is specific for ATP and ADP and is inhibit ed by geldanamycin, Mutation of four glycine residues within two propo sed ATP binding motifs diminishes both geldanamycin binding and the AT P-dependent conversion of hsp90 to a conformation capable of binding t he co-chaperone p23, Since p23 binding requires regions outside the 1- 221 domain of hsp90, these results indicate a common site for nucleoti des and geldanamycin that regulates the conformation of other hsp90 do mains.