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Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers

Author

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  • Fanjun Li

    (University of Massachusetts Amherst)

  • Monifa A. Fahie

    (University of Massachusetts Amherst)

  • Kaitlyn M. Gilliam

    (University of Massachusetts Amherst)

  • Ryan Pham

    (University of Massachusetts Amherst)

  • Min Chen

    (University of Massachusetts Amherst
    University of Massachusetts Amherst)

Abstract

Protein kinases play central roles in cellular regulation by catalyzing the phosphorylation of target proteins. Kinases have inherent structural flexibility allowing them to switch between active and inactive states. Quantitative characterization of kinase conformational dynamics is challenging. Here, we use nanopore tweezers to assess the conformational dynamics of Abl kinase domain, which is shown to interconvert between two major conformational states where one conformation comprises three sub-states. Analysis of kinase-substrate and kinase-inhibitor interactions uncovers the functional roles of relevant states and enables the elucidation of the mechanism underlying the catalytic deficiency of an inactive Abl mutant G321V. Furthermore, we obtain the energy landscape of Abl kinase by quantifying the population and transition rates of the conformational states. These results extend the view on the dynamic nature of Abl kinase and suggest nanopore tweezers can be used as an efficient tool for other members of the human kinome.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31215-5
    DOI: 10.1038/s41467-022-31215-5
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    1. 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.

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