Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein

Chem Biol. 2013 Dec 19;20(12):1469-80. doi: 10.1016/j.chembiol.2013.10.008. Epub 2013 Nov 14.

Abstract

Hsp70s are important cancer chaperones that act upstream of Hsp90 and exhibit independent anti-apoptotic activities. To develop chemical tools for the study of human Hsp70, we developed a homology model that unveils a previously unknown allosteric site located in the nucleotide binding domain of Hsp70. Combining structure-based design and phenotypic testing, we discovered a previously unknown inhibitor of this site, YK5. In cancer cells, this compound is a potent and selective binder of the cytosolic but not the organellar human Hsp70s and has biological activity partly by interfering with the formation of active oncogenic Hsp70/Hsp90/client protein complexes. YK5 is a small molecule inhibitor rationally designed to interact with an allosteric pocket of Hsp70 and represents a previously unknown chemical tool to investigate cellular mechanisms associated with Hsp70.

Publication types

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

MeSH terms

  • Allosteric Site / drug effects*
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism
  • Drug Discovery
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP70 Heat-Shock Proteins / chemistry
  • HSP70 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / metabolism
  • Heat Shock Transcription Factors
  • Humans
  • Models, Molecular
  • Protein Structure, Tertiary / drug effects
  • Structural Homology, Protein
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Transcription Factors