PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain.

ABSTRACT: Hsp70 proteins are a family of ancient and conserved chaperones. They play important roles in vital cellular processes, such as protein quality control and the stress response. Hsp70 proteins are a potential drug target for treatment of disease, particularly cancer. PES (2-phenylethynesulfonamide or pifithrin-μ) has been reported to be an inhibitor of Hsp70. However, the mechanism of PES inhibition is still unclear. In this study we found that PES can undergo a Michael addition reaction with Cys-574 and Cys-603 in the SBDα of human HspA1A (hHsp70), resulting in covalent attachment of a PES molecule to each Cys residue. We previously showed that glutathionylation of Cys-574 and Cys-603 affects the structure and function of hHsp70. In this study, PES modification showed similar structural an

SUBMITTER: Yang J 

PROVIDER: S-EPMC7948744 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature