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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 cocrystal 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.
Original language | English |
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Article number | e63586 |
Pages (from-to) | 1-49 |
Number of pages | 49 |
Journal | eLife |
Volume | 10 |
DOIs | |
Publication status | Published - 11 Feb 2021 |
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Dive into the research topics of 'The allosteric modulation of Complement C5 by knob domain peptides'. Together they form a unique fingerprint.Projects
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Dissecting complement resistance in Staphylococcus aureus
The Academy of Medical Sciences
1/09/21 → 31/08/23
Project: UK charity