Structural consensus among antibodies defines the antigen binding site
Open accessAbstract
The Complementarity Determining Regions (CDRs) of antibodies are assumed to account for the antigen recognition and binding and thus to contain also the antigen binding site. CDRs are typically discerned by searching for regions that are most different, in sequence or in structure, between different antibodies. Here, we show that ~20% of the antibody residues that actually bind the antigen fall outside the CDRs. However, virtually all antigen binding residues lie in regions of structural consensus across antibodies. Furthermore, we show that these regions of structural consensus which cover the antigen binding site are identifiable from the sequence of the antibody. Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically. Furthermore, antigen binding residues that fall outside of the structural consensus regions but within traditionally defined CDRs show a marginal energetic contribution to antigen binding. These findings allow for systematic and comprehensive identification of antigen binding sites, which can improve the understanding of antigenic interactions and may be useful in antibody engineering and B-cell epitope identification.
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About half of the 40-50 residues in the CDRs are in direct contact with the antigen, forming the paratope.
“About half of the 40–50 residues in the CDRs are in direct contact with the antigen, forming the paratope [157–159].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [159]
Framework residues can bury a substantial amount of surface area upon antigen-antibody complex formation.
“Analyses of high resolution crystal structures of antigen-antibody complexes show that the framework residues can bury a substantial amount of surface area upon complex formation [159, 160].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [159]
Tools such as Paratome can be used to identify positions in the framework region that might contribute to antigen recognition.
“Since not all paratope residues are constrained to the CDRs, tools such as Paratome [111, 159] can be used to identify positions in the framework region that might contribute to antigen recognition as well.”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [159]
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- Authors
- Kunik, V., Peters, B., & Ofran, Y.
- Affiliations
- Bar-Ilan University (IL)
- La Jolla Institute for Immunology (US)
- Corresponding author
- Ofran, Yanay
- ORCID
- Peters, Bjoern
- Venue
- PLoS Computational Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-02-23
- Volume
- 8
- Issue
- 2
- Pages
- e1002388
- ISSN
- 1553-734X (ISSN-L)
- 1553-7358
- PMC
- PMC3285572
- OpenAlex
- W2045080704
- Cited by
- 117
- References
- 40
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 13 · 2020: 8 · 2019: 9 · 2018: 11 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 9 · 2013: 7 · 2012: 2
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Computational Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (N01-AI-900048C, AI-900048C)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- hypervariable region, antibody structure, antibody engineering, antigen recognition
- MeSH terms
- Alanine, Antibodies, Antigen-Antibody Complex, Epitopes, Antigens, Automation, B-Lymphocytes, Binding Sites, Binding Sites, Antibody, Humans, Molecular Conformation, Mutation, Reproducibility of Results, Complementarity Determining Regions
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