ArticleCell chemical biology2024
Profiling of drug resistance in Src kinase at scale uncovers a regulatory network coupling autoinhibition and catalytic domain dynamics.
Article in Cell chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- High-resolution measurement of ERK activation state reveals determinants of BRAF regulation and drug sensitivity.bioRxiv : the preprint server for biology · 2026Article
- Overestimating zero-shot fitness prediction: Broad benchmarks mask local failures and practical limitations.bioRxiv : the preprint server for biology · 2026Article
- SynFit: Synergistic Contrastive Learning for Multi-Objective Protein Fitness Prediction and Optimization.bioRxiv : the preprint server for biology · 2026Article
- The allosteric landscape of the Src kinase.Science advances · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Amino acid substitutions at rheostat positions in the NaProtein science : a publication of the Protein Society · 2025Article
- Beyond Purification: Evolving Roles of Fusion Tags in Biotechnology.Current issues in molecular biology · 2025Review
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Article
- Mapping kinase domain resistance mechanisms for the MET receptor tyrosine kinase via deep mutational scanning.bioRxiv : the preprint server for biology · 2024Article
- Multiplexed profiling of intracellular protein abundance, activity, interactions and druggability with LABEL-seq.Nature methods · 2024Article
- Article
- Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.bioRxiv : the preprint server for biology · 2024Article
- Multiplexed, multimodal profiling of the intracellular activity, interactions, and druggability of protein variants using LABEL-seq.bioRxiv : the preprint server for biology · 2024Article
- Rheostats, toggles, and neutrals, Oh my! A new framework for understanding how amino acid changes modulate protein function.The Journal of biological chemistry · 2024Review
- All the mutations that are fit to die.Cell chemical biology · 2024Article
- ProteinGym: Large-Scale Benchmarks for Protein Design and Fitness Prediction.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Kinase inhibitors are effective cancer therapies, but resistance often limits clinical efficacy. Despite the cataloging of numerous resistance mutations, our understanding of kinase inhibitor resistance is still incomplete. Here, we comprehensively profiled the resistance of ∼3,500 Src tyrosine kinase mutants to four different ATP-competitive inhibitors. We found that ATP-competitive inhibitor resistance mutations are distributed throughout Src's catalytic domain. In addition to inhibitor contact residues, residues that participate in regulating Src's phosphotransferase activity were prone to the development of resistance. Unexpectedly, we found that a resistance-prone cluster of residues located on the top face of the N-terminal lobe of Src's catalytic domain contributes to autoinhibition by reducing catalytic domain dynamics, and mutations in this cluster led to resistance by lowering inhibitor affinity and promoting kinase hyperactivation. Together, our studies demonstrate how drug resistance profiling can be used to define potential resistance pathways and uncover new mechanisms of kinase regulation.
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