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Protein painting reveals solvent-excluded drug targets hidden within native protein–protein interfaces

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  • Alessandra Luchini

    (Center for Applied Proteomics and Molecular Medicine, George Mason University)

  • Virginia Espina

    (Center for Applied Proteomics and Molecular Medicine, George Mason University)

  • Lance A. Liotta

    (Center for Applied Proteomics and Molecular Medicine, George Mason University)

Abstract

Identifying the contact regions between a protein and its binding partners is essential for creating therapies that block the interaction. Unfortunately, such contact regions are extremely difficult to characterize because they are hidden inside the binding interface. Here we introduce protein painting as a new tool that employs small molecules as molecular paints to tightly coat the surface of protein–protein complexes. The molecular paints, which block trypsin cleavage sites, are excluded from the binding interface. Following mass spectrometry, only peptides hidden in the interface emerge as positive hits, revealing the functional contact regions that are drug targets. We use protein painting to discover contact regions between the three-way interaction of IL1β ligand, the receptor IL1RI and the accessory protein IL1RAcP. We then use this information to create peptides and monoclonal antibodies that block the interaction and abolish IL1β cell signalling. The technology is broadly applicable to discover protein interaction drug targets.

Suggested Citation

  • Alessandra Luchini & Virginia Espina & Lance A. Liotta, 2014. "Protein painting reveals solvent-excluded drug targets hidden within native protein–protein interfaces," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5413
    DOI: 10.1038/ncomms5413
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