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Allosteric nanobodies to study the interactions between SOS1 and RAS

Author

Listed:
  • Baptiste Fischer

    (CBMN
    European Institute of Chemistry and Biology (IECB))

  • Tomasz Uchański

    (VIB
    Vrije Universiteit Brussel)

  • Aidana Sheryazdanova

    (VIB-KU Leuven Center for Cancer Biology
    KU Leuven)

  • Simon Gonzalez

    (Vrije Universiteit Brussel)

  • Alexander N. Volkov

    (VIB
    VUB)

  • Elke Brosens

    (VIB
    Vrije Universiteit Brussel)

  • Thomas Zögg

    (VIB
    Vrije Universiteit Brussel)

  • Valentina Kalichuk

    (VIB
    Vrije Universiteit Brussel)

  • Steven Ballet

    (Vrije Universiteit Brussel)

  • Wim Versées

    (VIB
    Vrije Universiteit Brussel)

  • Anna A. Sablina

    (VIB-KU Leuven Center for Cancer Biology
    KU Leuven)

  • Els Pardon

    (VIB
    Vrije Universiteit Brussel)

  • Alexandre Wohlkönig

    (VIB
    Vrije Universiteit Brussel)

  • Jan Steyaert

    (VIB
    Vrije Universiteit Brussel)

Abstract

Protein-protein interactions (PPIs) are central in cell metabolism but research tools for the structural and functional characterization of these PPIs are often missing. Here we introduce broadly applicable immunization (Cross-link PPIs and immunize llamas, ChILL) and selection strategies (Display and co-selection, DisCO) for the discovery of diverse nanobodies that either stabilize or disrupt PPIs in a single experiment. We apply ChILL and DisCO to identify competitive, connective, or fully allosteric nanobodies that inhibit or facilitate the formation of the SOS1•RAS complex and modulate the nucleotide exchange rate on this pivotal GTPase in vitro as well as RAS signalling in cellulo. One of these connective nanobodies fills a cavity that was previously identified as the binding pocket for a series of therapeutic lead compounds. The long complementarity-determining region (CDR3) that penetrates this binding pocket serves as pharmacophore for extending the repertoire of potential leads.

Suggested Citation

  • Baptiste Fischer & Tomasz Uchański & Aidana Sheryazdanova & Simon Gonzalez & Alexander N. Volkov & Elke Brosens & Thomas Zögg & Valentina Kalichuk & Steven Ballet & Wim Versées & Anna A. Sablina & Els, 2024. "Allosteric nanobodies to study the interactions between SOS1 and RAS," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50349-2
    DOI: 10.1038/s41467-024-50349-2
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    References listed on IDEAS

    as
    1. P. Ann Boriack-Sjodin & S. Mariana Margarit & Dafna Bar-Sagi & John Kuriyan, 1998. "The structural basis of the activation of Ras by Sos," Nature, Nature, vol. 394(6691), pages 337-343, July.
    2. Roshanak Irannejad & Jin C. Tomshine & Jon R. Tomshine & Michael Chevalier & Jacob P. Mahoney & Jan Steyaert & Søren G. F. Rasmussen & Roger K. Sunahara & Hana El-Samad & Bo Huang & Mark von Zastrow, 2013. "Conformational biosensors reveal GPCR signalling from endosomes," Nature, Nature, vol. 495(7442), pages 534-538, March.
    3. Dean P. Staus & Ryan T. Strachan & Aashish Manglik & Biswaranjan Pani & Alem W. Kahsai & Tae Hun Kim & Laura M. Wingler & Seungkirl Ahn & Arnab Chatterjee & Ali Masoudi & Andrew C. Kruse & Els Pardon , 2016. "Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation," Nature, Nature, vol. 535(7612), pages 448-452, July.
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