@article{04d4bb7fed6f485facaf52cbf320961b,
title = "Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike",
abstract = "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 sub-lineage has gained in proportion relative to BA.1. Because spike (S) protein variations may underlie differences in their pathobiology, here we determine cryoelectron microscopy (cryo-EM) structures of the BA.2 S ectodomain and compare these with previously determined BA.1 S structures. BA.2 receptor-binding domain (RBD) mutations induce remodeling of the RBD structure, resulting in tighter packing and improved thermostability. Interprotomer RBD interactions are enhanced in the closed (or 3-RBD-down) BA.2 S, while the fusion peptide is less accessible to antibodies than in BA.1. Binding and pseudovirus neutralization assays reveal extensive immune evasion while defining epitopes of two outer RBD face-binding antibodies, DH1044 and DH1193, that neutralize both BA.1 and BA.2. Taken together, our results indicate that stabilization of the closed state through interprotomer RBD-RBD packing is a hallmark of the Omicron variant and show differences in key functional regions in the BA.1 and BA.2 S proteins.",
keywords = "CP: Microbiology, Omicron BA.2, SARS-CoV-2 spike, cryoelectron microscopy, fusion peptide, immune evasion, receptor binding domain",
author = "Victoria Stalls and Jared Lindenberger and Gobeil, {Sophie M.C.} and Rory Henderson and Rob Parks and Maggie Barr and Margaret Deyton and Mitchell Martin and Katarzyna Janowska and Xiao Huang and Aaron May and Micah Speakman and Esther Beaudoin and Bryan Kraft and Xiaozhi Lu and Edwards, {Robert J.} and Amanda Eaton and Montefiori, {David C.} and Williams, {Wilton B.} and Saunders, {Kevin O.} and Kevin Wiehe and Haynes, {Barton F.} and Priyamvada Acharya",
note = "Funding Information: cryo-EM data were collected at the Duke Krios at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (award number ECCS-2025064 ) as part of the National Nanotechnology Coordinated Infrastructure ( NNCI ). This study utilized the computational resources offered by Duke Research Computing ( http://rc.duke.edu ; NIH 1S10OD018164-01 ) at Duke University. This work was supported by NIH R01 AI145687 (P.A. and W.W.) and AI165147 (P.A. and R.C.H.) and NIH , NIAID , DMID grant P01 AI158571 (B.F.H.). Funding Information: cryo-EM data were collected at the Duke Krios at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (award number ECCS-2025064) as part of the National Nanotechnology Coordinated Infrastructure (NNCI). This study utilized the computational resources offered by Duke Research Computing (http://rc.duke.edu; NIH 1S10OD018164-01) at Duke University. This work was supported by NIH R01 AI145687 (P.A. and W.W.) and AI165147 (P.A. and R.C.H.) and NIH, NIAID, DMID grant P01 AI158571 (B.F.H.). V.S. and P.A. determined cryo-EM structures and prepared the first draft of the manuscript. J.L. purified RBD and spike proteins and performed surface plasmon resonance (SPR) experiments. V.S. S.M.-C.G. R.H. A.M. and P.A. analyzed structures. S.M.-C.G. performed immunoprecipitation assays. R.P. M.B. M.D. and M.M. performed ELISA assays. K.J. X.H. A.M. M.S. and E.B. expressed and purified proteins. R.J.E. performed negative stain electron microscopy (NSEM) analysis. K.W. and W.W. analyzed data. K.O.S. B.K. and X.L. provided key reagents. B.F.H. provided S RBD and S2 antibodies, supervised ELISA assays, and edited the manuscript. All authors reviewed and approved the manuscript. P.A. supervised the study and reviewed all data. B.F.H. K.O.S. B.K. X.L. R.J.E. S.M.-C.G. and P.A. are named in patents submitted on the SARS-CoV-2 monoclonal antibodies studied in this paper. Other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jun,
day = "28",
doi = "10.1016/j.celrep.2022.111009",
language = "English",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
number = "13",
}