7P78

SARS-CoV-2 spike protein in complex with sybody#15 and sybody#68 in a 1up/1up-out/1down conformation

Summary for 7P78

• Entry DOI: 10.2210/pdb7p78/pdb
• Related: 7P77 7P79 7P7A 7P7B
• EMDB information: 12083
• Descriptor: Spike glycoprotein, sybody#15, sybody#68, ... (7 entities in total)
• Functional Keywords: sars-cov-2 spike protein sybody, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV); More
• Total number of polymer chains: 8
• Total formula weight: 503528.13

Authors

Walter, J.D.,Hutter, C.A.J.,Garaeva, A.A.,Scherer, M.,Zimmermann, I.,Wyss, M.,Rheinberger, J.,Ruedin, Y.,Earp, J.C.,Egloff, P.,Sorgenfrei, M.,Huerlimann, L.M.,Gonda, I.,Meier, G.,Remm, S.,Thavarasah, S.,Zimmer, G.,Slotboom, D.J.,Paulino, C.,Plattet, P.,Seeger, M.A. (deposition date: 2021-07-19, release date: 2021-08-04, Last modification date: 2024-10-16)

Primary citation

Walter, J.D.,Scherer, M.,Hutter, C.A.J.,Garaeva, A.A.,Zimmermann, I.,Wyss, M.,Rheinberger, J.,Ruedin, Y.,Earp, J.C.,Egloff, P.,Sorgenfrei, M.,Hurlimann, L.M.,Gonda, I.,Meier, G.,Remm, S.,Thavarasah, S.,van Geest, G.,Bruggmann, R.,Zimmer, G.,Slotboom, D.J.,Paulino, C.,Plattet, P.,Seeger, M.A.
Biparatopic sybodies neutralize SARS-CoV-2 variants of concern and mitigate drug resistance.
Embo Rep., 23:e54199-e54199, 2022

PubMed Abstract: The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS-CoV-2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo-EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri-bispecific fusion constructs that exhibit up to 100- and 1,000-fold increase in neutralization potency, respectively. Cryo-EM of the sybody-spike complex additionally reveals a novel up-out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants.

PubMed: 35253970
DOI: 10.15252/embr.202154199

Experimental method

ELECTRON MICROSCOPY (3.32 Å)