8SAK

BtCoV-422 in complex with neutralizing antibody JC57-11

Summary for 8SAK

• Entry DOI: 10.2210/pdb8sak/pdb
• EMDB information: 40272 40306 40310
• Descriptor: Spike glycoprotein, JC57-11 Fab heavy chain, JC57-11 Fab light chain, ... (7 entities in total)
• Functional Keywords: coronavirus, mers, neutralizing, antibody, mers-like, merbecovirus, bat, virus, cdrh3, rbd, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: unclassified Merbecovirus; More
• Total number of polymer chains: 5
• Total formula weight: 486302.15

Authors

McFadden, E.,McLellan, J.S. (deposition date: 2023-04-01, release date: 2023-10-04, Last modification date: 2024-10-23)

Primary citation

Tse, L.V.,Hou, Y.J.,McFadden, E.,Lee, R.E.,Scobey, T.D.,Leist, S.R.,Martinez, D.R.,Meganck, R.M.,Schafer, A.,Yount, B.L.,Mascenik, T.,Powers, J.M.,Randell, S.H.,Zhang, Y.,Wang, L.,Mascola, J.,McLellan, J.S.,Baric, R.S.
A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
Sci Transl Med, 15:eadg5567-eadg5567, 2023

PubMed Abstract: The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)-related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV//GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/M protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV-neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo-electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.

PubMed: 37756379
DOI: 10.1126/scitranslmed.adg5567

Experimental method

ELECTRON MICROSCOPY (3 Å)