Allosteric nanobodies to study the interactions between SOS1 and RAS

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 Pardon, Alexandre Wohlkönig and Jan Steyaert ()
Additional contact information
Baptiste Fischer: CBMN
Tomasz Uchański: VIB
Aidana Sheryazdanova: VIB-KU Leuven Center for Cancer Biology
Simon Gonzalez: Vrije Universiteit Brussel
Alexander N. Volkov: VIB
Elke Brosens: VIB
Thomas Zögg: VIB
Valentina Kalichuk: VIB
Steven Ballet: Vrije Universiteit Brussel
Wim Versées: VIB
Anna A. Sablina: VIB-KU Leuven Center for Cancer Biology
Els Pardon: VIB
Alexandre Wohlkönig: VIB
Jan Steyaert: VIB

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50349-2

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