ArticleProceedings of the National Academy of Sciences of the United States of America2014
The structural analysis of shark IgNAR antibodies reveals evolutionary principles of immunoglobulins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 93 citations in OpenAlex.
- In vitro selection of VNAR antibodies using bioinformatics-based library design and cDNA display.Biotechnology reports (Amsterdam, Netherlands) · 2026Article
- New insights into antibody structure with implications for specificity, variable region restriction and isotype choice.Nature reviews. Immunology · 2025Review
- Construction and application of a large capacity VNAR library from the whitespotted bamboo shark (Acta pharmaceutica Sinica. B · 2025Article
- Unusual traits shape the architecture of the Ig ancestor molecule.Communications biology · 2025Article
- Expression Analysis of Heavy-Chain-Only Antibodies in Cloudy Catshark and Japanese Bullhead Shark.Marine drugs · 2025Article
- VNAR: shark single-domain antibodies for the new era of medical biotechnology.Frontiers in immunology · 2025Review
- Characteristics and Genomic Localization of Nurse Shark (International journal of molecular sciences · 2024Article
- Functional Divergence in the Affinity and Stability of Non-Canonical Cysteines and Non-Canonical Disulfide Bonds: Insights from a VHH and VNAR Study.International journal of molecular sciences · 2024Article
- Immunoglobulin constant regions provide stabilization to the paratope and enforce epitope specificity.The Journal of biological chemistry · 2024Article
- Nanobodies in the fight against infectious diseases: repurposing nature's tiny weapons.World journal of microbiology & biotechnology · 2024Review
- Novel Approach for Obtaining Variable Domain of New Antigen Receptor with Different Physicochemical Properties from Japanese Topeshark (Marine drugs · 2023Article
- Evolution of the Immunoglobulin Isotypes-Variations of Biophysical Properties among Animal Classes.Biomolecules · 2023Article
- Isolation and Characterization of Targeting-HBsAg VNAR Single Domain Antibodies from Whitespotted Bamboo Sharks (Marine drugs · 2023Article
- Affimers and nanobodies as molecular probes and their applications in imaging.Journal of cell science · 2022Article
- Marine-derived microbes and molecules for drug discovery.Inflammation and regeneration · 2022Review
- Special focus issue: passive immunization.Human vaccines & immunotherapeutics · 2022Article
- A Bionic-Homodimerization Strategy for Optimizing Modulators of Protein-Protein Interactions: From Statistical Mechanics Theory to Potential Clinical Translation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- The influence of antibody humanization on shark variable domain (VNAR) binding site ensembles.Frontiers in immunology · 2022Article
- Comparing Antibody Interfaces to Inform Rational Design of New Antibody Formats.Frontiers in molecular biosciences · 2022Article
- Elasmobranch microbiomes: emerging patterns and implications for host health and ecology.Animal microbiome · 2021Review
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
Sharks and other cartilaginous fish are the phylogenetically oldest living organisms that rely on antibodies as part of their adaptive immune system. They produce the immunoglobulin new antigen receptor (IgNAR), a homodimeric heavy chain-only antibody, as a major part of their humoral adaptive immune response. Here, we report the atomic resolution structure of the IgNAR constant domains and a structural model of this heavy chain-only antibody. We find that despite low sequence conservation, the basic Ig fold of modern antibodies is already present in the evolutionary ancient shark IgNAR domains, highlighting key structural determinants of the ubiquitous Ig fold. In contrast, structural differences between human and shark antibody domains explain the high stability of several IgNAR domains and allowed us to engineer human antibodies for increased stability and secretion efficiency. We identified two constant domains, C1 and C3, that act as dimerization modules within IgNAR. Together with the individual domain structures and small-angle X-ray scattering, this allowed us to develop a structural model of the complete IgNAR molecule. Its constant region exhibits an elongated shape with flexibility and a characteristic kink in the middle. Despite the lack of a canonical hinge region, the variable domains are spaced appropriately wide for binding to multiple antigens. Thus, the shark IgNAR domains already display the well-known Ig fold, but apart from that, this heavy chain-only antibody employs unique ways for dimerization and positioning of functional modules.
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