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| Title | SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. |
|---|---|
| Journal, issue, pages | Nature, Vol. 588, Issue 7839, Page 682-687, Year 2020 |
| Publish date | Oct 12, 2020 |
 Authors | Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / Davide F Robbiani / Michel C Nussenzweig / Anthony P West / Pamela J Bjorkman /   |
| PubMed Abstract | The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute ...The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2. |
 External links | Nature / PubMed:33045718 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 1.65 - 4.4 Å |
| Structure data | EMDB-22729, PDB-7k8s: EMDB-22730, PDB-7k8t: EMDB-22731, PDB-7k8u: EMDB-22732, PDB-7k8v: EMDB-22733, PDB-7k8w: EMDB-22734, PDB-7k8x: EMDB-22735, PDB-7k8y: EMDB-22736, PDB-7k8z: EMDB-22737, PDB-7k90:  PDB-7k8m:  PDB-7k8n:  PDB-7k8o:  PDB-7k8p:  PDB-7k8q:  PDB-7k8r: |
| Chemicals |  ChemComp-NAG:  ChemComp-SO4:  ChemComp-GOL:  ChemComp-PEG:  ChemComp-HOH: |
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 Keywords |  VIRAL PROTEIN/IMMUNE SYSTEM / Human Neutralizing Antibody / SARS-CoV-2 / Receptor Binding Domain / COVID-19 / VIRAL PROTEIN-IMMUNE SYSTEM complex / IMMUNE SYSTEM / spike glycoprotein / monoclonal antibody / neutralizing antibody / PROTEIN-IMMUNE SYSTEM complex |
