Hsp90 is an ubiquitous, evolutionarily conserved protein chaperone. In addition to its role in the cellular stress response, Hsp90 is required for the proper function of a wide variety of signal transduction molecules. C. elegans Hsp90 is encoded by the
daf-21 gene, and mutations in
daf-21 affect larval viability, dauer formation, chemotaxis, fertility, and lifespan. In all other species studied to date, the activity of Hsp90 is selectively inhibited by the drug geldanamycin. However, treatment of C. elegans with geldanamycin produced no discernable phenotypes, despite the high degree of sequence similarity shared with Hsp90 from other species. In vitro drug binding studies proved consistent with this observation; geldanamycin-coupled beads failed to interact with Daf-21 either from worm protein extracts or when expressed in rabbit reticulocyte extracts. Prior X-ray crystallographic analyses of human Hsp90 identified an ATP-binding pocket in the amino-terminal domain of the protein, and defined this pocket as the site of geldanamycin binding. We found that the amino-terminal domain of Daf-21 likewise binds to ATP, but fails to bind geldanamycin. Therefore, Daf-21 is unique among characterized Hsp90 orthologs in its ability to discriminate between ATP and geldanamycin. This property might reflect evolutionary selection, because geldanamycin is a natural product from the common soil bacterium Streptomyces hygroscopicus. Also, the selectivity of Daf-21 has implications for the development of human drug resistance to geldanamycin, which is currently in clinical trials.