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To produce high-affinity peptides, we previously isolated autonomous 3\u20136 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 &gt;50 \u00c5 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.<\/jats:p>","DOI":"10.7554\/elife.63586","type":"journal-article","created":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T08:04:22Z","timestamp":1613030662000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.63586","source":"Crossref","is-referenced-by-count":28,"title":["The allosteric modulation of complement C5 by knob domain peptides"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4508-5322","authenticated-orcid":true,"given":"Alex","family":"Macpherson","sequence":"first","affiliation":[{"name":"UCB, Slough, United Kingdom"},{"name":"Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8425-3704","authenticated-orcid":true,"given":"Maisem","family":"Laabei","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4495-8689","authenticated-orcid":true,"given":"Zainab","family":"Ahdash","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A","family":"Graewert","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, Hamburg Unit, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R","family":"Birtley","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika-Sarah ED","family":"Schulze","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Crennell","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Holmes","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladas","family":"Oleinikovas","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per H","family":"Nilsson","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"},{"name":"Department of Chemistry and Biomedicine, Linnaeus University, Kalmar, Sweden"},{"name":"Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-7329","authenticated-orcid":true,"given":"James","family":"Snowden","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Ellis","sequence":"additional","affiliation":[{"name":"UCB, Slough, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Eirik","family":"Mollnes","sequence":"additional","affiliation":[{"name":"Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway"},{"name":"Research Laboratory, Bod\u00f8 Hospital, K.G. 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