Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

Discovering the secrets of Hsp90 binding

Geldanamycin is an antibiotic that binds to Hsp90 and inhibits its adenosine triphosphate binding and activity as a chaperone. A derivative of geldanamycin (GM) is the Hsp90 inhibitor 17-allylaminogeldanamycin (17-AAG), which preferentially kills tumor cells and is in phase I clinical trials. Hsp90 is found in all cell types, but it has been unclear how the preferential killing of tumor cells by 17-AAG is accomplished. In the September 25 Nature, Adeela Kamal and colleagues at Conforma Therapeutics Corporation report that Hsp90 from tumor cells binds with higher affinity to 17-AAG and that this is due to Hsp90 being in multichaperone complexes in these cells. (Nature, 425:407-410, September 25, 2003)

Kamal et al. performed competitive binding assays using increasing concentrations of 17-AAG to inhibit the binding of Hsp90 to GM-biotin and observed that Hsp90 from tumor cells had a 50% inhibitory concentration (IC50) of 6 nM compared with 400-600 nM for Hsp90 from control cells. Measurements comparing the binding of adenosine triphosphate (ATP) to Hsp90 also showed a lower IC50 for tumor Hsp90, revealing that Hsp90 in tumor cells had a significantly higher binding affinity for 17-AAG. Hsp90 assembles in multichaperone complexes by interacting with many cochaperone proteins (e.g., p23, Hop), and co-immunoprecipitation of Hsp90 demonstrated that Hsp90 from tumor cells is present in more of these complexes. Hsp90 tumor complexes also showed a higher ATPase activity (something that Hsp90 chaperone function is dependent on) that was inhibited by 17-AAG. In addition, in vitro reconstituted Hsp90 complexes showed an increased apparent affinity for 17-AAG-12 nM for Hsp90 alone rising to 600 nM when complexed. The authors then performed these experiments in mice and in clinical cancer and observed a similar pattern of 17-AAG binding to in vivo tumor Hsp90.

"Our data show that Hsp90 in tumor cells exists in a functionally distinct molecular form. [Hsp90 could be the] Achilles heel of tumor cells, driving the selective accumulation and bioactivity of pharmacological Hsp90 inhibitors, and making tumor Hsp90 a unique cancer target," conclude the authors.


  1. 1.

    Heat shock protein 90 as a molecular target for cancer therapeutics

  2. 2.

    Nature, []

  3. 3.

    Conforma Therapeutics, []

  4. 4.

    Hsp90: chaperoning signal transduction

Download references


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Secko, D. Discovering the secrets of Hsp90 binding. Genome Biol 4, spotlight-20030925-01 (2003).

Download citation


  • Adenosine Triphosphate
  • Kill Tumor Cell
  • Hsp90 Inhibitor
  • Geldanamycin
  • Hsp90 Chaperone