Crystal Structure of an Hsp90-geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent

Cell. 1997 Apr 18;89(2):239-50. doi: 10.1016/s0092-8674(00)80203-2.

Abstract

The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are protooncogenic 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 A 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibiotics, Antineoplastic / chemistry*
  • Antibiotics, Antineoplastic / metabolism
  • Benzoquinones
  • Cattle
  • Conserved Sequence
  • Crystallography, X-Ray
  • HSP90 Heat-Shock Proteins / chemistry*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Quinones / chemistry*
  • Quinones / metabolism
  • Sequence Alignment

Substances

  • Antibiotics, Antineoplastic
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Quinones
  • geldanamycin