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Single-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore

Author

Listed:
  • Ki-Baek Jeong

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Critical Diseases Diagnostics Convergence Research Center, KRIBB)

  • Minju Ryu

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    KRIBB School of Bioscience, University of Science and Technology)

  • Jin-Sik Kim

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Critical Diseases Diagnostics Convergence Research Center, KRIBB)

  • Minsoo Kim

    (Sungkyunkwan University)

  • Jejoong Yoo

    (Sungkyunkwan University)

  • Minji Chung

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Sohee Oh

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Gyunghee Jo

    (Institute for Basic Science (IBS))

  • Seong-Gyu Lee

    (Institute for Basic Science (IBS))

  • Ho Min Kim

    (Institute for Basic Science (IBS)
    Korea Advanced Institute of Science and Technology (KAIST))

  • Mi-Kyung Lee

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    Critical Diseases Diagnostics Convergence Research Center, KRIBB
    KRIBB School of Bioscience, University of Science and Technology)

  • Seung-Wook Chi

    (Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    KRIBB School of Bioscience, University of Science and Technology
    Sungkyunkwan University)

Abstract

In drug discovery, efficient screening of protein-drug interactions (PDIs) is hampered by the limitations of current biophysical approaches. Here, we develop a biological nanopore sensor for single-molecule detection of proteins and PDIs using the pore-forming toxin YaxAB. Using this YaxAB nanopore, we demonstrate label-free, single-molecule detection of interactions between the anticancer Bcl-xL protein and small-molecule drugs as well as the Bak-BH3 peptide. The long funnel-shaped structure and nanofluidic characteristics of the YaxAB nanopore enable the electro-osmotic trapping of diverse folded proteins and high-resolution monitoring of PDIs. Distinctive nanopore event distributions observed in the two-dimensional (ΔI/Io-versus-IN) plot illustrate the ability of the YaxAB nanopore to discriminate individual small-molecule drugs bound to Bcl-xL from non-binders. Taken together, our results present the YaxAB nanopore as a robust platform for label-free, ultrasensitive, single-molecule detection of PDIs, opening up a possibility for low-cost, highly efficient drug discovery against diverse drug targets.

Suggested Citation

  • Ki-Baek Jeong & Minju Ryu & Jin-Sik Kim & Minsoo Kim & Jejoong Yoo & Minji Chung & Sohee Oh & Gyunghee Jo & Seong-Gyu Lee & Ho Min Kim & Mi-Kyung Lee & Seung-Wook Chi, 2023. "Single-molecule fingerprinting of protein-drug interaction using a funneled biological nanopore," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37098-4
    DOI: 10.1038/s41467-023-37098-4
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    References listed on IDEAS

    as
    1. Fanjun Li & Monifa A. Fahie & Kaitlyn M. Gilliam & Ryan Pham & Min Chen, 2022. "Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Nicole Stéphanie Galenkamp & Misha Soskine & Jos Hermans & Carsten Wloka & Giovanni Maglia, 2018. "Direct electrical quantification of glucose and asparagine from bodily fluids using nanopores," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
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    2. Fanjun Li & Monifa A. Fahie & Kaitlyn M. Gilliam & Ryan Pham & Min Chen, 2022. "Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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