PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain
Copyright policy )PES inhibits human-inducible Hsp70 by covalent targeting of cysteine residues in the substrate-binding domain
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.
- University of Chinese Academy of Sciences China (People's Republic of)
- Chinese Academy of Sciences China (People's Republic of)
- Institute of Biophysics China (People's Republic of)
Models, Molecular, Protein Conformation, alpha-Helical, Sulfonamides, Binding Sites, Sequence Homology, Amino Acid, Gene Expression, Glutathione, Recombinant Proteins, Kinetics, Mutation, Humans, HSP70 Heat-Shock Proteins, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cysteine, Protein Processing, Post-Translational, Sequence Alignment, Research Article, Protein Binding
Models, Molecular, Protein Conformation, alpha-Helical, Sulfonamides, Binding Sites, Sequence Homology, Amino Acid, Gene Expression, Glutathione, Recombinant Proteins, Kinetics, Mutation, Humans, HSP70 Heat-Shock Proteins, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cysteine, Protein Processing, Post-Translational, Sequence Alignment, Research Article, Protein Binding
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).13 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!