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Cell Rep . Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class

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  • Cell Rep . Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class


    Cell Rep


    . 2021 Mar 19;108950.
    doi: 10.1016/j.celrep.2021.108950. Online ahead of print.
    Modular basis for potent SARS-CoV-2 neutralization by a prevalent VH1-2-derived antibody class


    Micah Rapp 1 , Yicheng Guo 2 , Eswar R Reddem 1 , Jian Yu 3 , Lihong Liu 3 , Pengfei Wang 3 , Gabriele Cerutti 1 , Phinikoula Katsamba 4 , Jude S Bimela 4 , Fabiana A Bahna 4 , Seetha M Mannepalli 4 , Baoshan Zhang 5 , Peter D Kwong 6 , Yaoxing Huang 3 , David D Ho 3 , Lawrence Shapiro 7 , Zizhang Sheng 8



    Affiliations

    Abstract

    Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determine the structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three use VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy-chain N53I-enhancing binding and light-chain tyrosines recognizing F486RBD. Despite these similarities, class members bind both RBD-up and -down conformations of the spike, with a subset of antibodies using elongated CDRH3s to recognize glycan N343 on a neighboring RBD-a quaternary interaction accommodated by an increase in RBD separation of up to 12 ?. The VH1-2 antibody class, thus, uses modular recognition encoded by modular genetic elements to effect potent neutralization, with the VH-gene component specifying recognition of RBD and the CDRH3 component specifying quaternary interactions.

    Keywords: COVID-19; RBD; SARS-CoV-2; multi-donor antibody class; neutralizing antibody; quaternary recognition; spike.

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