articleScience AdvancesFeb 11, 2026GOLD OA

The allosteric landscape of the Src kinase

TBToni BeltranMMMohsin M. NaqviAJAndré J. FaureBLBen Lehner

Centre for Genomic Regulation · Instituto de Biomedicina de Valencia · +3 more institutions

PubMed
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Abstract

Enzymes catalyze the reactions of life and are the targets of many drugs. Most inhibitors bind conserved active sites, frequently lacking specificity. Targeting allosteric sites can increase specificity, reduce toxicity, and allow fine-tuning of activity; however, most allosteric sites in enzymes are unmapped. Here, we present a comprehensive experimental allosteric map of the Src protein kinase. We quantify the effects of more than 50,000 single and double amino acid substitutions on activity and abundance and use thermodynamic modeling to disentangle changes in fold stability and catalysis. The comprehensive energy landscape reveals that allostery across the kinase domain is extensive, directionally biased,…

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4

Topics & keywords

Topics
Keywords
  • Allosteric regulation
  • Druggability
  • Allosteric enzyme
  • Enzyme
  • Kinase
  • Proto-oncogene tyrosine-protein kinase Src
  • Protein kinase domain
UN Sustainable Development Goals
  • Affordable and clean energy
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