Journal article
The allosteric modulation of Complement C5 by knob domain peptides
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 4.4MB, Terms of use)
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- Publisher copy:
- 10.7554/eLife.63586
Authors
- Publisher:
- eLife Sciences Publications
- Journal:
- eLife More from this journal
- Volume:
- 10
- Article number:
- e63586
- Publication date:
- 2021-03-18
- Acceptance date:
- 2021-02-11
- DOI:
- EISSN:
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2050-084X
- Pmid:
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33570492
- Language:
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English
- Keywords:
- Pubs id:
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1161491
- Local pid:
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pubs:1161491
- Deposit date:
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2021-03-16
- ARK identifier:
Terms of use
- Copyright holder:
- A Macpherson et al.
- Copyright date:
- 2021
- Rights statement:
- © 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.
- Licence:
- CC Attribution (CC BY)
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