1. Immunology and Inflammation
  2. Structural Biology and Molecular Biophysics
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The allosteric modulation of Complement C5 by knob domain peptides

  1. Alex Macpherson  Is a corresponding author
  2. Maisem Laabei
  3. Zainab Ahdash
  4. Melissa A Graewert
  5. James R Birtley
  6. Monika-Sarah ED Schulze
  7. Susan Crennell
  8. Sarah A Robinson
  9. Ben Holmes
  10. Vladas Oleinikovas
  11. Per H Nilsson
  12. James Snowden
  13. Victoria Ellis
  14. Tom Eirik Mollnes
  15. Charlotte M Deane
  16. Dmitri Svergun
  17. Alastair DG Lawson
  18. Jean MH van den Elsen  Is a corresponding author
  1. University of Bath, United Kingdom
  2. UCB-Celltech, United Kingdom
  3. EMBL Hamburg, Germany
  4. University of Oxford, United Kingdom
  5. Oslo University hospital, Sweden
  6. University of Oslo, Norway
  7. EMBL/DESY, Germany
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Cite this article as: eLife 2021;10:e63586 doi: 10.7554/eLife.63586

Abstract

Bovines have evolved a subset of antibodies with ultra-long CDRH3 regions that harbour cysteine-rich knob domains. To produce high affinity peptides, we previously isolated autonomous 3-6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 Å from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

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Author details

  1. Alex Macpherson

    Biology & Biochemistry, University of Bath, Bath, United Kingdom
    For correspondence
    Alex.MacPherson@ucb.com
    Competing interests
    Alex Macpherson, employee of UCB and may hold shares and/or stock options.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4508-5322

  2. Maisem Laabei

    Biology and Biochemistry, University of Bath, Bath, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8425-3704

  3. Zainab Ahdash

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Zainab Ahdash, employee of UCB and may hold shares and/or stock options.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4495-8689

  4. Melissa A Graewert

    Biological Small Angle Scattering, EMBL Hamburg, Hamburg, Germany
    Competing interests
    No competing interests declared.

  5. James R Birtley

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    James R Birtley, employee of UCB and may hold shares and/or stock options.

  6. Monika-Sarah ED Schulze

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Monika-Sarah ED Schulze, employee of UCB and may hold shares and/or stock options.

  7. Susan Crennell

    Biology & Biochemistry, University of Bath, Bath, United Kingdom
    Competing interests
    No competing interests declared.

  8. Sarah A Robinson

    Statistics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.

  9. Ben Holmes

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Ben Holmes, employee of UCB and may hold shares and/or stock options.

  10. Vladas Oleinikovas

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Vladas Oleinikovas, employee of UCB and may hold shares and/or stock options.

  11. Per H Nilsson

    Immunology, Oslo University hospital, Oslo, Sweden
    Competing interests
    No competing interests declared.

  12. James Snowden

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    James Snowden, employee of UCB and may hold shares and/or stock options.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4855-7329

  13. Victoria Ellis

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Victoria Ellis, employee of UCB and may hold shares and/or stock options.

  14. Tom Eirik Mollnes

    Department of Immunology, University of Oslo, Oslo, Norway
    Competing interests
    Tom Eirik Mollnes, T.E.M is a Board member of Ra Pharmaceuticals, Inc.

  15. Charlotte M Deane

    Department of Statistics, University of Oxford, Oxford, United Kingdom
    Competing interests
    Charlotte M Deane, Reviewing editor, eLife.

  16. Dmitri Svergun

    Biological Small Angle Scattering, EMBL/DESY, Hamburg, Germany
    Competing interests
    No competing interests declared.

  17. Alastair DG Lawson

    Immunology, UCB-Celltech, Slough, United Kingdom
    Competing interests
    Alastair DG Lawson, employee of UCB and may hold shares and/or stock options.

  18. Jean MH van den Elsen

    Biology & Biochemistry, University of Bath, Bath, United Kingdom
    For correspondence
    bssjmhve@bath.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0367-1956

Funding

No specific external funding was received for this work.

Reviewing Editor

  1. John Kuriyan, University of California, Berkeley, United States

Publication history

  1. Received: September 29, 2020
  2. Accepted: February 11, 2021
  3. Accepted Manuscript published: February 11, 2021 (version 1)

Copyright

© 2021, Macpherson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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