ArticleThe Journal of biological chemistry
PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 21 citations in OpenAlex.
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- Biochemical characterization of the full-length isoform of soluble adenylyl cyclase.The Journal of biological chemistry · 2025Article
- Comprehensive Analysis of the Role of Heat Shock Proteins in the Immune Microenvironment and Clinical Significance of Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- HSPA8 inhibitors augment cancer chemotherapeutic effectiveness via potentiating necroptosis.Molecular biology of the cell · 2024Article
- Pifithrin-µ Induces Stress Granule Formation, Regulates Cell Survival, and Rewires Cellular Signaling.Cells · 2024Article
- HSPA8 acts as an amyloidase to suppress necroptosis by inhibiting and reversing functional amyloid formation.Cell research · 2023Article
- Article
- Prevention of High Glucose-Mediated EMT by Inhibition of Hsp70 Chaperone.International journal of molecular sciences · 2021Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 and functional effects on hHsp70 to glutathionylation. Further, we found that susceptibility to PES modification is influenced by changes in the conformational dynamics of the SBDα, such as are induced by interaction with adjacent domains, allosteric changes, and mutations. This study provides new avenues for development of covalent inhibitors of hHsp70.
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