Related Experiment Video

Updated: Jun 23, 2026

Analyzing Protein Dynamics Using Hydrogen Exchange Mass Spectrometry
11:37

Analyzing Protein Dynamics Using Hydrogen Exchange Mass Spectrometry

Published on: November 29, 2013

Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent

C E Stebbins1, A A Russo, C Schneider

  • 1Department of Biochemistry and Structural Biology, Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.

Cell
|April 18, 1997
PubMed

Insights

Geldanamycin, an antibiotic targeting heat shock protein 90 (Hsp90), inhibits cancer-promoting protein activation. Structural analysis reveals Hsp90

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Oncology

Background:

  • Heat shock protein 90 (Hsp90) is crucial for activating eukaryotic protein kinases and nuclear hormone receptors, many implicated in cancer.
  • Protooncogenic proteins often rely on Hsp90 for their function and stability.
  • Inhibiting Hsp90 can lead to the degradation of these cancer-promoting substrates.

Purpose of the Study:

  • To elucidate the structural basis of Hsp90 inhibition by geldanamycin.
  • To understand how geldanamycin binding affects Hsp90's conformational maturation function.
  • To explore the implications for cancer therapy.

Main Methods:

  • X-ray crystallography to determine the structure of the geldanamycin-binding domain of Hsp90.
  • Biochemical assays to study Hsp90-mediated conformational maturation.
  • Analysis of conserved structural features within the Hsp90 binding pocket.

Main Results:

  • The structure of the Hsp90-geldanamycin complex revealed a deep, conserved binding pocket.
  • Geldanamycin adopts a compact, turn-like conformation within this pocket.
  • The pocket's structure suggests it interacts with Hsp90 substrates, participating in conformational maturation.

Conclusions:

  • Geldanamycin inhibits Hsp90 by binding to a conserved pocket, interfering with substrate conformational maturation.
  • This mechanism underlies geldanamycin's antiproliferative and antitumor effects.
  • The Hsp90 binding pocket is a potential target for developing novel cancer therapeutics.

More Related Videos

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay06:51

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

Published on: July 21, 2021

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors07:57

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors

Published on: January 20, 2023

Related Concept Videos

Protein Complex Assembly02:41

Protein Complex Assembly

Proteins can form homomeric complexes with another unit of the same protein or heteromeric complexes with different types.  Most protein complexes self-assemble spontaneously via ordered pathways, while some proteins need assembly factors that guide their proper assembly. Despite the crowded intracellular environment, proteins usually interact with their correct partners and form functional complexes.
Many viruses self-assemble into a fully functional unit using the infected host cell to...
Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...