The allosteric modulation of Complement C5 by knob domain peptides
- University of Bath, United Kingdom
- UCB-Celltech, United Kingdom
- EMBL Hamburg, Germany
- University of Oxford, United Kingdom
- Oslo University hospital, Sweden
- University of Oslo, Norway
- EMBL/DESY, Germany
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.
Data availability
Structural datasets presented in this study have been made publicly available in the Protein Data Bank (PDB) and Small Angle Scattering Biological Data Bank (SASBDB)
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Crystal structure C5-K8 complexProtein Data Bank, 7AD7.
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Crystal structure of C5-K92 complexProtein Data Bank, 7AD6.
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SAXS data and models of C5-bovine knob domain peptidesSmall Angle Scattering Biological Data Bank, SASDJA6.
Article and author information
Author details
Jean MH van den Elsen
Funding
No specific external funding was received for this work.
Reviewing Editor
- John Kuriyan, University of California, Berkeley, United States
Publication history
- Received: September 29, 2020
- Accepted: February 11, 2021
- Accepted Manuscript published: February 11, 2021 (version 1)
- Version of Record published: March 18, 2021 (version 2)
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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The allosteric modulation of Complement C5 by knob domain peptides
eLife 10:e63586.
https://doi.org/10.7554/eLife.63586
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