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Structure paper

TitleSARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Journal, issue, pagesNature, Vol. 588, Issue 7839, Page 682-687, Year 2020
Publish dateOct 12, 2020
AuthorsChristopher 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 AbstractThe 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 linksNature / PubMed:33045718 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.65 - 4.4 Å
Structure data

EMDB-22729, PDB-7k8s:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C002 (state 1)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-22730, PDB-7k8t:
Structure of the SARS-CoV-2 S 6P trimer in complex with the human neutralizing antibody Fab fragment, C002 (State 2)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-22731, PDB-7k8u:
Structure of the SARS-CoV-2 S 6P trimer in complex with the human neutralizing antibody Fab fragment, C104
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-22732, PDB-7k8v:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C110
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-22733, PDB-7k8w:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C119
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-22734, PDB-7k8x:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C121 (State 1)
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-22735, PDB-7k8y:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C121 (State 2)
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-22736, PDB-7k8z:
Structure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C135
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-22737, PDB-7k90:
Structure of the SARS-CoV-2 S 6P trimer in complex with the human neutralizing antibody Fab fragment, C144
Method: EM (single particle) / Resolution: 3.24 Å

PDB-7k8m:
Structure of the SARS-CoV-2 receptor binding domain in complex with the human neutralizing antibody Fab fragment, C102
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

PDB-7k8n:
Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C102
Method: X-RAY DIFFRACTION / Resolution: 1.65 Å

PDB-7k8o:
Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C002
Method: X-RAY DIFFRACTION / Resolution: 1.95 Å

PDB-7k8p:
Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C110
Method: X-RAY DIFFRACTION / Resolution: 1.8 Å

PDB-7k8q:
Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C121
Method: X-RAY DIFFRACTION / Resolution: 2.0 Å

PDB-7k8r:
Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C135
Method: X-RAY DIFFRACTION / Resolution: 2.0 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

ChemComp-HOH:
WATER / Water

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL 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

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