Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent

TLDR

Hsp90 is essential for activating proto‑oncogenic kinases and hormone receptors, making it a key cancer target, and the antibiotic geldanamycin exerts antitumor activity by binding Hsp90 and blocking its chaperone function. The crystal structure shows a 15‑Å deep, evolutionarily conserved pocket in Hsp90’s N‑terminal domain that accommodates geldanamycin in a turn‑like conformation, suggesting the pocket normally binds a substrate segment and participates in the refolding cycle.

Abstract

The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are proto-oncogenic and play a prominent role in cancer. The geldanamycin antibiotic has antiproliferative and antitumor effects, as it binds to Hsp90, inhibits the Hsp90-mediated conformational maturation/refolding reaction, and results in the degradation of Hsp90 substrates. The structure of the geldanamycin-binding domain of Hsp90 (residues 9–232) reveals a pronounced pocket, 15 Å deep, that is highly conserved across species. Geldanamycin binds inside this pocket, adopting a compact structure similar to that of a polypeptide chain in a turn conformation. This, and the pocket's similarity to substrate-binding sites, suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/ refolding reaction.