7K8R

Crystal structure of an anti-SARS-CoV-2 human neutralizing antibody Fab fragment, C135

Summary for 7K8R

• Entry DOI: 10.2210/pdb7k8r/pdb
• Descriptor: C135 Fab Heavy Chain, C135 Fab Light Chain, GLYCEROL, ... (4 entities in total)
• Functional Keywords: human neutralizing antibody, sars-cov-2, receptor binding domain, covid-19, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 47488.83

Authors

Jette, C.A.,Barnes, C.O.,Bjorkman, P.J. (deposition date: 2020-09-27, release date: 2020-10-21, Last modification date: 2024-10-23)

Primary citation

Barnes, C.O.,Jette, C.A.,Abernathy, M.E.,Dam, K.A.,Esswein, S.R.,Gristick, H.B.,Malyutin, A.G.,Sharaf, N.G.,Huey-Tubman, K.E.,Lee, Y.E.,Robbiani, D.F.,Nussenzweig, M.C.,West Jr., A.P.,Bjorkman, P.J.
SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Nature, 588:682-687, 2020

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 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.

PubMed: 33045718
DOI: 10.1038/s41586-020-2852-1

Experimental method

X-RAY DIFFRACTION (2 Å)