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

Apr 5, 2021

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

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

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. 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 Å. 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.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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About The Expert

Micah Rapp

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Yicheng Guo

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

Eswar R Reddem

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Jian Yu

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

Lihong Liu

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

Pengfei Wang

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

Gabriele Cerutti

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Phinikoula Katsamba

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Jude S Bimela

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Fabiana A Bahna

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Seetha M Mannepalli

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.

Baoshan Zhang

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Peter D Kwong

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Yaoxing Huang

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

David D Ho

Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.

Lawrence Shapiro

Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lss8@columbia.edu.

Zizhang Sheng

Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: zs2248@cumc.columbia.edu.

References

PubMed