7JWB

SARS CoV2 Spike ectodomain with engineered trimerized VH binder

Summary for 7JWB

• Entry DOI: 10.2210/pdb7jwb/pdb
• EMDB information: 22514
• Descriptor: autonomous human heavy chain variable domain, Spike glycoprotein (2 entities in total)
• Functional Keywords: spike, vh, sars, cov2, viral protein-immune system complex, viral protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 445524.15

Authors

QCRG Structural Biology Consortium (deposition date: 2020-08-25, release date: 2020-10-07, Last modification date: 2024-11-13)

Primary citation

Bracken, C.J.,Lim, S.A.,Solomon, P.,Rettko, N.J.,Nguyen, D.P.,Zha, B.S.,Schaefer, K.,Byrnes, J.R.,Zhou, J.,Lui, I.,Liu, J.,Pance, K.,Zhou, X.X.,Leung, K.K.,Wells, J.A.
Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2.
Nat.Chem.Biol., 17:113-121, 2021

PubMed Abstract: Neutralizing agents against SARS-CoV-2 are urgently needed for the treatment and prophylaxis of COVID-19. Here, we present a strategy to rapidly identify and assemble synthetic human variable heavy (VH) domains toward neutralizing epitopes. We constructed a VH-phage library and targeted the angiotensin-converting enzyme 2 (ACE2) binding interface of the SARS-CoV-2 Spike receptor-binding domain (Spike-RBD). Using a masked selection approach, we identified VH binders to two non-overlapping epitopes and further assembled these into multivalent and bi-paratopic formats. These VH constructs showed increased affinity to Spike (up to 600-fold) and neutralization potency (up to 1,400-fold) on pseudotyped SARS-CoV-2 virus when compared to standalone VH domains. The most potent binder, a trivalent VH, neutralized authentic SARS-CoV-2 with a half-maximal inhibitory concentration (IC) of 4.0 nM (180 ng ml). A cryo-EM structure of the trivalent VH bound to Spike shows each VH domain engaging an RBD at the ACE2 binding site, confirming our original design strategy.

PubMed: 33082574
DOI: 10.1038/s41589-020-00679-1

Experimental method

ELECTRON MICROSCOPY (6 Å)