ArticleACS chemical biology2018
A Local Allosteric Network in Heat Shock Protein 70 (Hsp70) Links Inhibitor Binding to Enzyme Activity and Distal Protein-Protein Interactions.
Article in ACS chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Hsp70 is phosphorylated in a conserved response to DNA damage and contributes to cell cycle control.eLife · 2026Article
- New inhibitors of themSphere · 2026Article
- A conserved Hsp70 phosphorylation regulates cell cycle progression after DNA damage.bioRxiv : the preprint server for biology · 2025Article
- Hsc70-4: An unanticipated mediator of dsRNA internalization inScience advances · 2025Article
- Overview of host-directed antiviral targets for future research and drug development.Acta pharmaceutica Sinica. B · 2025Review
- N-myc-Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma.Cancer research · 2023Article
- Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma.Cell chemical biology · 2022Article
- A campaign targeting a conserved Hsp70 binding site uncovers how subcellular localization is linked to distinct biological activities.Cell chemical biology · 2022Article
- The dynamics of t1 adenosine binding on human Argonaute 2: Understanding recognition with conformational selection.Protein science : a publication of the Protein Society · 2022Article
- Probing Allosteric Hsp70 Inhibitors by Molecular Modelling Studies to Expedite the Development of Novel Combined F508del CFTR Modulators.Pharmaceuticals (Basel, Switzerland) · 2021Article
- HSP70s in Breast Cancer: Promoters of Tumorigenesis and Potential Targets/Tools for Therapy.Cells · 2021Review
- New perspectives in cancer drug development: computational advances with an eye to design.RSC medicinal chemistry · 2021Review
- Machine Learning Prediction of Allosteric Drug Activity from Molecular Dynamics.The journal of physical chemistry letters · 2021Article
- Exported plasmodial J domain protein, PFE0055c, and PfHsp70-x form a specific co-chaperone-chaperone partnership.Cell stress & chaperones · 2021Article
- Role of the J Domain Protein Family in the Survival and Pathogenesis of Plasmodium falciparum.Advances in experimental medicine and biology · 2021Review
- Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98.Bioorganic & medicinal chemistry letters · 2020Article
- Tryptophan scanning mutagenesis as a way to mimic the compound-bound state and probe the selectivity of allosteric inhibitors in cells.Chemical science · 2020Article
- Allosteric Regulation at the Crossroads of New Technologies: Multiscale Modeling, Networks, and Machine Learning.Frontiers in molecular biosciences · 2020Review
- Modulating protein-protein interaction networks in protein homeostasis.Current opinion in chemical biology · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Allosteric inhibitors can be more difficult to optimize without an understanding of how their binding influences the conformational motions of the target. Here, we used an integrated computational and experimental approach to probe the molecular mechanism of an allosteric inhibitor of heat shock protein 70 (Hsp70). The anticancer compound, MKT-077, is known to bind a conserved site in members of the Hsp70 family, which favors the ADP-bound state and interferes with a protein-protein interaction (PPI) at long range. However, the binding site does not overlap with either the nucleotide-binding cleft or the PPI contact surface, so its mechanism is unclear. To this end, we modeled Hsp70's internal dynamics and studied how MKT-077 alters local sampling of its allosteric states. The results pointed to a set of concerted motions between five loops in Hsp70's nucleotide-binding domain (NBD), surrounding the MKT-077 binding site. To test this prediction, we mutated key residues and monitored chaperone activities in vitro. Together, the results indicate that MKT-077 interacts with loop222 to favor a pseudo-ADP bound conformer of Hsp70's NBD, even when ATP is present. We used this knowledge to synthesize an analog of MKT-077 that would better prevent motions of loop222 and confirmed that it had improved antiproliferative activity in breast cancer cells. These results provide an example of how to unlock and leverage the complex mechanisms of allosteric inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.