The allosteric modulation of complement c5 by knob domain peptides
Macpherson, Alex; Laabei, Maisem; Ahdash, Zainab; Graewert, Melissa Ann; Birtley, James R.; Schulze, Monika-Sarah E.D.; Crennell, Susan; Robinson, Sarah A.; Holmes, Ben; Oleinikovas, Vladas; Nilsson, Per H.; Snowden, James; Ellis, Victoria; Mollnes, Tom Eirik; Deane, Charlotte M.; Svergun, Dmitri I.; Lawson, Alastair D.G.; van den Elsen, Jean
Peer reviewed, Journal article
Published version
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https://hdl.handle.net/11250/2778550Utgivelsesdato
2021Metadata
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Bovines have evolved a subset of antibodies with ultra-long heavy chain complementarity determining 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.