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The allosteric modulation of Complement C5 by knob domain peptides

DOI: 10.7554/eLife.63586 DOI Help

Authors: Alex Macpherson (University of Bath) , Maisem Laabei (University of Bath) , Zainab Ahdash (UCB-Celltech) , Melissa A Graewert (EMBL Hamburg) , James R Birtley (UCB-Celltech) , Monika-Sarah Schulze (UCB-Celltech) , Susan Crennell (University of Bath) , Sarah A Robinson (University of Oxford) , Ben Holmes (UCB-Celltech) , Vladas Oleinikovas (UCB-Celltech) , Per H. Nilsson (Oslo University Hospital) , James Snowden (UCB-Celltech) , Victoria Ellis (UCB-Celltech) , Tom Eirik Mollnes (University of Oslo) , Charlotte M. Deane (University of Oxford) , Dmitri Svergun (EMBL/DESY) , Alastair D. G. Lawson (UCB-Celltech) , Jean M. H. Van Den Elsen (University of Bath)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Elife , VOL 10

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 20029

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 10/03/2021 08:56

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)