tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Yicheng Guo[SUP] 2 [/SUP], Eswar R Reddem[SUP] 1 [/SUP], Jian Yu[SUP] 3 [/SUP], Lihong Liu[SUP] 3 [/SUP], Pengfei Wang[SUP] 3 [/SUP], Gabriele Cerutti[SUP] 1 [/SUP], Phinikoula Katsamba[SUP] 4 [/SUP], Jude S Bimela[SUP] 4 [/SUP], Fabiana A Bahna[SUP] 4 [/SUP], Seetha M Mannepalli[SUP] 4 [/SUP], Baoshan Zhang[SUP] 5 [/SUP], Peter D Kwong[SUP] 6 [/SUP], Yaoxing Huang[SUP] 3 [/SUP], David D Ho[SUP] 3 [/SUP], Lawrence Shapiro[SUP] 7 [/SUP], Zizhang Sheng[SUP] 8 [/SUP]
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 F486[SUB]RBD[/SUB]. 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.
. 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[SUP] 1 [/SUP], Yicheng Guo[SUP] 2 [/SUP], Eswar R Reddem[SUP] 1 [/SUP], Jian Yu[SUP] 3 [/SUP], Lihong Liu[SUP] 3 [/SUP], Pengfei Wang[SUP] 3 [/SUP], Gabriele Cerutti[SUP] 1 [/SUP], Phinikoula Katsamba[SUP] 4 [/SUP], Jude S Bimela[SUP] 4 [/SUP], Fabiana A Bahna[SUP] 4 [/SUP], Seetha M Mannepalli[SUP] 4 [/SUP], Baoshan Zhang[SUP] 5 [/SUP], Peter D Kwong[SUP] 6 [/SUP], Yaoxing Huang[SUP] 3 [/SUP], David D Ho[SUP] 3 [/SUP], Lawrence Shapiro[SUP] 7 [/SUP], Zizhang Sheng[SUP] 8 [/SUP]
Affiliations
- PMID: 33794145
- DOI: 10.1016/j.celrep.2021.108950
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 F486[SUB]RBD[/SUB]. 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.