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Mechanistic principles of an ultra-long bovine CDR reveal strategies for antibody design

Author

Listed:
  • Hristo L. Svilenov

    (Center for Protein Assemblies and Department Chemie, Technische Universität München)

  • Julia Sacherl

    (Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich)

  • Ulrike Protzer

    (Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich
    German Center for Infection Research, Munich partner site)

  • Martin Zacharias

    (Center for Protein Assemblies and the Department Physik, Technische Universität München)

  • Johannes Buchner

    (Center for Protein Assemblies and Department Chemie, Technische Universität München)

Abstract

Antibodies bind antigens via flexible loops called complementarity-determining regions (CDRs). These are usually 6-20 residues long. However, some bovine antibodies have ultra-long CDRs comprising more than 50 residues organized in a stalk and a disulfide-rich knob. The design features of this structural unit and its influence on antibody stability remained enigmatic. Here, we show that the stalk length is critical for the folding and stability of antibodies with an ultra-long CDR and that the disulfide bonds in the knob do not contribute to stability; they are important for organizing the antigen-binding knob structure. The bovine ultra-long CDR can be integrated into human antibody scaffolds. Furthermore, mini-domains from de novo design can be reformatted as ultra-long CDRs to create unique antibody-based proteins neutralizing SARS-CoV-2 and the Alpha variant of concern with high efficiency. Our findings reveal basic design principles of antibody structure and open new avenues for protein engineering.

Suggested Citation

  • Hristo L. Svilenov & Julia Sacherl & Ulrike Protzer & Martin Zacharias & Johannes Buchner, 2021. "Mechanistic principles of an ultra-long bovine CDR reveal strategies for antibody design," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27103-z
    DOI: 10.1038/s41467-021-27103-z
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    1. Devin Sok & Khoa M. Le & Melissa Vadnais & Karen L. Saye-Francisco & Joseph G. Jardine & Jonathan L. Torres & Zachary T. Berndsen & Leopold Kong & Robyn Stanfield & Jennifer Ruiz & Alejandra Ramos & C, 2017. "Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows," Nature, Nature, vol. 548(7665), pages 108-111, August.
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