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Mechanistic principles of an ultra-long bovine CDR reveal strategies for antibody design.
Svilenov, Hristo L; Sacherl, Julia; Protzer, Ulrike; Zacharias, Martin; Buchner, Johannes.
  • Svilenov HL; Center for Protein Assemblies and Department Chemie, Technische Universität München, 85748, Garching, Germany. hristo.svilenov@tum.de.
  • Sacherl J; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Protzer U; Institute of Virology, Technical University of Munich / Helmholtz Zentrum Munich, Munich, Germany.
  • Zacharias M; German Center for Infection Research, Munich partner site, Munich, Germany.
  • Buchner J; Center for Protein Assemblies and the Department Physik, Technische Universität München, 85748, Garching, Germany.
Nat Commun ; 12(1): 6737, 2021 11 18.
Article in English | MEDLINE | ID: covidwho-1526077
ABSTRACT
Antibodies bind antigens via flexible loops called complementarity-determining regions (CDRs). These are usually 6-20 residues long. However, some bovine antibodies have ultra-long CDRs comprising more than 50 residues organized in a stalk and a disulfide-rich knob. The design features of this structural unit and its influence on antibody stability remained enigmatic. Here, we show that the stalk length is critical for the folding and stability of antibodies with an ultra-long CDR and that the disulfide bonds in the knob do not contribute to stability; they are important for organizing the antigen-binding knob structure. The bovine ultra-long CDR can be integrated into human antibody scaffolds. Furthermore, mini-domains from de novo design can be reformatted as ultra-long CDRs to create unique antibody-based proteins neutralizing SARS-CoV-2 and the Alpha variant of concern with high efficiency. Our findings reveal basic design principles of antibody structure and open new avenues for protein engineering.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Complementarity Determining Regions / SARS-CoV-2 Topics: Variants Limits: Animals Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-27103-z

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Complementarity Determining Regions / SARS-CoV-2 Topics: Variants Limits: Animals Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-27103-z