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The allosteric modulation of Complement C5 by knob domain peptides

Authors :
Sarah Schulze
Alastair D. G. Lawson
James Snowden
Victoria Ellis
Maisem Laabei
Sarah Robinson
Susan J. Crennell
Charlotte M. Deane
Jean M. H. van den Elsen
James R. Birtley
Dmitri I. Svergun
Ben Holmes
Vladas Oleinikovas
Tom Eirik Mollnes
Melissa A. Graewert
Per H. Nilsson
Zainab Ahdash
Alex Macpherson
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

To overcome limited germline combinatorial diversity, bovines have evolved a subset of antibodies with ultra-long CDRH3 regions that harbour cysteine-rich knob domains. To produce affinity-maturated 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........0967975d5e3c30a7d0fc992b18812e15
Full Text :
https://doi.org/10.1101/2020.10.24.353714