7S83

Crystal structure of SARS CoV-2 Spike Receptor Binding Domain in complex with shark neutralizing VNARs ShAb01 and ShAb02

Summary for 7S83

• Entry DOI: 10.2210/pdb7s83/pdb
• Descriptor: ShAb02 VNAR, Spike protein S1, ShAb01 VNAR, ... (6 entities in total)
• Functional Keywords: shark antibody, ignar, vnar, sars cov-2, spike protein, receptor binding domain, immune system, immune system-viral protein complex, immune system/viral protein
• Biological source: Ginglymostoma cirratum (nurse shark); More
• Total number of polymer chains: 3
• Total formula weight: 52834.38

Authors

Chen, W.-H.,Hajduczki, A.,Dooley, H.M.,Joyce, M.G. (deposition date: 2021-09-17, release date: 2022-11-23, Last modification date: 2023-10-25)

Primary citation

Chen, W.H.,Hajduczki, A.,Martinez, E.J.,Bai, H.,Matz, H.,Hill, T.M.,Lewitus, E.,Chang, W.C.,Dawit, L.,Peterson, C.E.,Rees, P.A.,Ajayi, A.B.,Golub, E.S.,Swafford, I.,Dussupt, V.,David, S.,Mayer, S.V.,Soman, S.,Kuklis, C.,Corbitt, C.,King, J.,Choe, M.,Sankhala, R.S.,Thomas, P.V.,Zemil, M.,Wieczorek, L.,Hart, T.,Duso, D.,Kummer, L.,Yan, L.,Sterling, S.L.,Laing, E.D.,Broder, C.C.,Williams, J.K.,Davidson, E.,Doranz, B.J.,Krebs, S.J.,Polonis, V.R.,Paquin-Proulx, D.,Rolland, M.,Reiley, W.W.,Gromowski, G.D.,Modjarrad, K.,Dooley, H.,Joyce, M.G.
Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity.
Nat Commun, 14:580-580, 2023

PubMed Abstract: Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

PubMed: 36737435
DOI: 10.1038/s41467-023-36106-x

Experimental method

X-RAY DIFFRACTION (2.52 Å)