Abstract
Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein homeostasis. Hsp70’s chaperone activity is coordinated by intra-molecular interactions between its two domains, as well as inter-molecular interactions between Hsp70 and its co-chaperones. Each of these contacts represents a potential opportunity for the development of chemical inhibitors. To illustrate this concept, we review three classes of recently identified molecules that bind distinct pockets on Hsp70. Although all three compounds share the ability to interrupt core biochemical functions of Hsp70, they stabilize different conformers. Accordingly, each compound appears to interrupt a specific subset of inter- and intra-molecular interactions. Thus, an accurate definition of an Hsp70 inhibitor may require a particularly detailed understanding of the molecule’s binding site and its effects on protein-protein interactions.
Keywords: Chaperone, Protein folding, Proteostasis, Irreversible inhibitors, Dynamics, Protein-protein interactions.
Current Topics in Medicinal Chemistry
Title:Targeting Allosteric Control Mechanisms in Heat Shock Protein 70 (Hsp70)
Volume: 16 Issue: 25
Author(s): Xiaokai Li, Hao Shao, Isabelle R. Taylor and Jason E. Gestwicki
Affiliation:
Keywords: Chaperone, Protein folding, Proteostasis, Irreversible inhibitors, Dynamics, Protein-protein interactions.
Abstract: Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein homeostasis. Hsp70’s chaperone activity is coordinated by intra-molecular interactions between its two domains, as well as inter-molecular interactions between Hsp70 and its co-chaperones. Each of these contacts represents a potential opportunity for the development of chemical inhibitors. To illustrate this concept, we review three classes of recently identified molecules that bind distinct pockets on Hsp70. Although all three compounds share the ability to interrupt core biochemical functions of Hsp70, they stabilize different conformers. Accordingly, each compound appears to interrupt a specific subset of inter- and intra-molecular interactions. Thus, an accurate definition of an Hsp70 inhibitor may require a particularly detailed understanding of the molecule’s binding site and its effects on protein-protein interactions.
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Cite this article as:
Li Xiaokai, Shao Hao, Taylor R. Isabelle and Gestwicki E. Jason, Targeting Allosteric Control Mechanisms in Heat Shock Protein 70 (Hsp70), Current Topics in Medicinal Chemistry 2016; 16 (25) . https://dx.doi.org/10.2174/1568026616666160413140911
DOI https://dx.doi.org/10.2174/1568026616666160413140911 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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