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

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 () and Seung-Wook Chi ()
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Ki-Baek Jeong: Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Minju Ryu: Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jin-Sik Kim: Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (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)
Mi-Kyung Lee: Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seung-Wook Chi: Division of Biomedical Research, Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37098-4

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