Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike

Victoria Stalls; Jared Lindenberger; Sophie M.C. Gobeil; Rory Henderson; Rob Parks; Maggie Barr; Margaret Deyton; Mitchell Martin; Katarzyna Janowska; Xiao Huang; Aaron May; Micah Speakman; Esther Beaudoin; Bryan Kraft; Xiaozhi Lu; Robert J. Edwards; Amanda Eaton; David C. Montefiori; Wilton B. Williams; Kevin O. Saunders; Kevin Wiehe; Barton F. Haynes; Priyamvada Acharya

doi:10.1016/j.celrep.2022.111009

Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike

Victoria Stalls, Jared Lindenberger, Sophie M.C. Gobeil, Rory Henderson, Rob Parks, Maggie Barr, Margaret Deyton, Mitchell Martin, Katarzyna Janowska, Xiao Huang, Aaron May, Micah Speakman, Esther Beaudoin, Bryan Kraft, Xiaozhi Lu, Robert J. Edwards, Amanda Eaton, David C. Montefiori, Wilton B. Williams, Kevin O. SaundersKevin Wiehe, Barton F. Haynes, Priyamvada Acharya

Division of Pulmonary & Critical Care Medicine

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English
Article number	111009
Journal	Cell Reports
Volume	39
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2022.111009
State	Published - Jun 28 2022

Keywords

CP: Microbiology
Omicron BA.2
SARS-CoV-2 spike
cryoelectron microscopy
fusion peptide
immune evasion
receptor binding domain

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10.1016/j.celrep.2022.111009

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Stalls, V., Lindenberger, J., Gobeil, S. M. C., Henderson, R., Parks, R., Barr, M., Deyton, M., Martin, M., Janowska, K., Huang, X., May, A., Speakman, M., Beaudoin, E., Kraft, B., Lu, X., Edwards, R. J., Eaton, A., Montefiori, D. C., Williams, W. B., ... Acharya, P. (2022). Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike. Cell Reports, 39(13), Article 111009. https://doi.org/10.1016/j.celrep.2022.111009

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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 = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = jun,

day = "28",

doi = "10.1016/j.celrep.2022.111009",

language = "English",

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Stalls, V, Lindenberger, J, Gobeil, SMC, Henderson, R, Parks, R, Barr, M, Deyton, M, Martin, M, Janowska, K, Huang, X, May, A, Speakman, M, Beaudoin, E, Kraft, B, Lu, X, Edwards, RJ, Eaton, A, Montefiori, DC, Williams, WB, Saunders, KO, Wiehe, K, Haynes, BF & Acharya, P 2022, 'Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike', Cell Reports, vol. 39, no. 13, 111009. https://doi.org/10.1016/j.celrep.2022.111009

TY - JOUR

T1 - Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike

AU - Stalls, Victoria

AU - Lindenberger, Jared

AU - Gobeil, Sophie M.C.

AU - Henderson, Rory

AU - Parks, Rob

AU - Barr, Maggie

AU - Deyton, Margaret

AU - Martin, Mitchell

AU - Janowska, Katarzyna

AU - Huang, Xiao

AU - May, Aaron

AU - Speakman, Micah

AU - Beaudoin, Esther

AU - Kraft, Bryan

AU - Lu, Xiaozhi

AU - Edwards, Robert J.

AU - Eaton, Amanda

AU - Montefiori, David C.

AU - Williams, Wilton B.

AU - Saunders, Kevin O.

AU - Wiehe, Kevin

AU - Haynes, Barton F.

AU - Acharya, Priyamvada

PY - 2022/6/28

Y1 - 2022/6/28

N2 - 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.

AB - 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.

KW - CP: Microbiology

KW - Omicron BA.2

KW - SARS-CoV-2 spike

KW - cryoelectron microscopy

KW - fusion peptide

KW - immune evasion

KW - receptor binding domain

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U2 - 10.1016/j.celrep.2022.111009

DO - 10.1016/j.celrep.2022.111009

M3 - Article

C2 - 35732171

AN - SCOPUS:85132857329

SN - 2639-1856

VL - 39

JO - Cell Reports

JF - Cell Reports

IS - 13

M1 - 111009

ER -

Cryo-EM structures of SARS-CoV-2 Omicron BA.2 spike

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Keywords

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