Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

A novel allosteric means of inhibiting heat shock 70 proteins

Sadlish, Heather and Hassan, Asm Quamrul and Zhou, Wenlai and Kirby, Christina and Schuhmann, Tim and Studer, Christian and Chang, Lena and Hoepfner, Dominic and Sellers, William and Movva, Rao and Aust, Thomas and Riedl, Ralph and Quinn, Christopher and Krastel, Philipp and Schmitt, Esther and Baird, Jason and Chung, Franklin and Chen, Jinyun and Schitter, Anne and Pagliarini, Raymond and Chen, Yaoyu and Quinn, D and Mayer, Matthias and Kityk, Roman (2014) A novel allosteric means of inhibiting heat shock 70 proteins. Chemistry and Biology.

Abstract

The highly conserved heat shock 70 proteins (HSP70) play an integral role in the chaperone network where ATP-driven cycles of protein folding are carefully controlled. HSP70 dysregulation has been implicated in numerous diseases including cancer and neurodegeneration, however, elucidating the precise role of HSP70 in the cellular context using genetic tools are hampered by the redundancy and intricate regulation of the chaperone network. Through yeast chemogenomic profiling we identified a novel natural product, novolactone, with a unique means of altering HSP70 activity. The compound does not compete with ATP or HSP40, but allosterically inhibits HSP70 ATPase activity through a selective covalent interaction. Co-crystalization with novolactone reveals a novel binding pocket that is conserved between HSP70 and HSC70, and treatment of mammalian cells leads to degradation of HSP90 client proteins. Thus, this small molecule is a valuable tool to explore the cellular requirements for the heat shock 70 chaperones in a disease context.

Item Type: Article
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9686

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.