8HRD

Crystal structure of the receptor binding domain of SARS-CoV-2 Delta variant in complex with IMCAS74 Fab and W14 Fab

Summary for 8HRD

• Entry DOI: 10.2210/pdb8hrd/pdb
• Descriptor: Spike protein S1, IMCAS74 Fab heavy chain, IMCAS74 Fab light chain, ... (7 entities in total)
• Functional Keywords: complex, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 20
• Total formula weight: 487973.09

Authors

Zhao, R.C.,Wu, L.L.,Han, P. (deposition date: 2022-12-15, release date: 2023-12-20, Last modification date: 2024-10-23)

Primary citation

Rao, X.,Zhao, R.,Tong, Z.,Guo, S.,Peng, W.,Liu, K.,Li, S.,Wu, L.,Tong, J.,Chai, Y.,Han, P.,Wang, F.,Jia, P.,Li, Z.,Zhao, X.,Li, D.,Zhang, R.,Zhang, X.,Zou, W.,Li, W.,Wang, Q.,Gao, G.F.,Wu, Y.,Dai, L.,Gao, F.
Defining a de novo non-RBM antibody as RBD-8 and its synergistic rescue of immune-evaded antibodies to neutralize Omicron SARS-CoV-2.
Proc.Natl.Acad.Sci.USA, 120:e2314193120-e2314193120, 2023

PubMed Abstract: Currently, monoclonal antibodies (MAbs) targeting the SARS-CoV-2 receptor binding domain (RBD) of spike (S) protein are classified into seven classes based on their binding epitopes. However, most of these antibodies are seriously impaired by SARS-CoV-2 Omicron and its subvariants, especially the recent BQ.1.1, XBB and its derivatives. Identification of broadly neutralizing MAbs against currently circulating variants is imperative. In this study, we identified a "breathing" cryptic epitope in the S protein, named as RBD-8. Two human MAbs, BIOLS56 and IMCAS74, were isolated recognizing this epitope with broad neutralization abilities against tested sarbecoviruses, including SARS-CoV, pangolin-origin coronaviruses, and all the SARS-CoV-2 variants tested (Omicron BA.4/BA.5, BQ.1.1, and XBB subvariants). Searching through the literature, some more RBD-8 MAbs were defined. More importantly, BIOLS56 rescues the immune-evaded antibody, RBD-5 MAb IMCAS-L4.65, by making a bispecific MAb, to neutralize BQ.1 and BQ.1.1, thereby producing an MAb to cover all the currently circulating Omicron subvariants. Structural analysis reveals that the neutralization effect of RBD-8 antibodies depends on the extent of epitope exposure, which is affected by the angle of antibody binding and the number of up-RBDs induced by angiotensin-converting enzyme 2 binding. This cryptic epitope which recognizes non- receptor binding motif (non-RBM) provides guidance for the development of universal therapeutic antibodies and vaccines against COVID-19.

PubMed: 38109549
DOI: 10.1073/pnas.2314193120

Experimental method

X-RAY DIFFRACTION (2.86 Å)