ArticleChemical science2020
Tryptophan scanning mutagenesis as a way to mimic the compound-bound state and probe the selectivity of allosteric inhibitors in cells.
Article in Chemical science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Article
- Design of multi-target peptide modulators for protein chaperone networks.Structure (London, England : 1993) · 2025Article
- Chemoproteogenomic stratification of the missense variant cysteinome.Nature communications · 2024Article
- A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13.ACS chemical biology · 2024Article
- Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.Journal of the American Chemical Society · 2024Article
- Using a Function-First "Scout Fragment"-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes.Journal of the American Chemical Society · 2024Article
- Peptide-based molecules for the disruption of bacterial Hsp70 chaperones.Current opinion in chemical biology · 2023Review
- Article
- Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma.Cell chemical biology · 2022Article
- An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.Cell chemical biology · 2022Article
- Two entry tunnels in mouse TAAR9 suggest the possibility of multi-entry tunnels in olfactory receptors.Scientific reports · 2022Article
- Biophysical and biochemical properties of PHGDH revealed by studies on PHGDH inhibitors.Cellular and molecular life sciences : CMLS · 2021Article
- 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
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Authors and funding
13 authors.
Funding
Abstract
Understanding the selectivity of a small molecule for its target(s) in cells is an important goal in chemical biology and drug discovery. One powerful way to address this question is with dominant negative (DN) mutants, in which an active site residue in the putative target is mutated. While powerful, this approach is less straightforward for allosteric sites. Here, we introduce tryptophan scanning mutagenesis as an expansion of this idea. As a test case, we focused on the challenging drug target, heat shock cognate protein 70 (Hsc70), and its allosteric inhibitor JG-98. Structure-based modelling predicted that mutating Y149W in human Hsc70 or Y145W in the bacterial ortholog DnaK would place an indole side chain into the allosteric pocket normally occupied by the compound. Indeed, we found that the tryptophan mutants acted as if they were engaged with JG-98. We then used DnaK Y145W to suggest that this protein may be an anti-bacterial target. Indeed, we found that DnaK inhibitors have minimum inhibitory concentration (MIC) values <0.125 μg mL
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