ArticleeLife2021
The allosteric modulation of complement C5 by knob domain peptides.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- Modulator-induced conformational changes in complement C5, implications for function and drug design.Frontiers in immunology · 2026Article
- Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire.PLoS pathogens · 2024Article
- The impact of exchanging the light and heavy chains on the structures of bovine ultralong antibodies.Acta crystallographica. Section F, Structural biology communications · 2024Article
- HIV envelope trimers and gp120 as immunogens to induce broadly neutralizing antibodies in cows.bioRxiv : the preprint server for biology · 2024Article
- Modular design of bi- and multi-specific knob domain fusions.Frontiers in immunology · 2024Article
- The smallest functional antibody fragment: Ultralong CDR H3 antibody knob regions potently neutralize SARS-CoV-2.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Cattle-derived knob paratopes grafted onto peripheral loops of the IgG1 Fc region enable the generation of a novel symmetric bispecific antibody format.Frontiers in immunology · 2023Article
- Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into their in-vivo functions.Computational and structural biotechnology journal · 2023Article
- Serum albumin binding knob domains engineered within a VFrontiers in immunology · 2023Article
- Phage Display of Bovine Ultralong CDRH3.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Germline-Encoded Positional Cysteine Polymorphisms Enhance Diversity in Antibody Ultralong CDR H3 Regions.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Multifaceted Activities of Seven Nanobodies against Complement C4b.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Milking the Cow: Cattle-Derived Chimeric Ultralong CDR-H3 Antibodies and Their Engineered CDR-H3-Only Knobbody Counterparts Targeting Epidermal Growth Factor Receptor Elicit Potent NK Cell-Mediated Cytotoxicity.Frontiers in immunology · 2021Article
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Authors and funding
18 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.