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TitleOmicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 4958, Year 2022
Publish dateAug 24, 2022
AuthorsZhennan Zhao / Jingya Zhou / Mingxiong Tian / Min Huang / Sheng Liu / Yufeng Xie / Pu Han / Chongzhi Bai / Pengcheng Han / Anqi Zheng / Lutang Fu / Yuanzhu Gao / Qi Peng / Ying Li / Yan Chai / Zengyuan Zhang / Xin Zhao / Hao Song / Jianxun Qi / Qihui Wang / Peiyi Wang / George F Gao /
PubMed AbstractOmicron SARS-CoV-2 is rapidly spreading worldwide. To delineate the impact of emerging mutations on spike's properties, we performed systematic structural analyses on apo Omicron spike and its ...Omicron SARS-CoV-2 is rapidly spreading worldwide. To delineate the impact of emerging mutations on spike's properties, we performed systematic structural analyses on apo Omicron spike and its complexes with human ACE2 or S309 neutralizing antibody (NAb) by cryo-EM. The Omicron spike preferentially adopts the one-RBD-up conformation both before and after ACE2 binding, which is in sharp contrast to the orchestrated conformational changes to create more up-RBDs upon ACE2 binding as observed in the prototype and other four variants of concern (VOCs). Furthermore, we found that S371L, S373P and S375F substitutions enhance the stability of the one-RBD-up conformation to prevent exposing more up-RBDs triggered by ACE2 binding. The increased stability of the one-RBD-up conformation restricts the accessibility of S304 NAb, which targets a cryptic epitope in the closed conformation, thus facilitating the immune evasion by Omicron. These results expand our understanding of Omicron spike's conformation, receptor binding and antibody evasion mechanism.
External linksNat Commun / PubMed:36002453 / PubMed Central
MethodsEM (single particle)
Resolution2.66 - 3.11 Å
Structure data

EMDB-33690, PDB-7y9s:
Cryo-EM structure of apo SARS-CoV-2 Omicron spike protein (S-2P-GSAS)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-33697, PDB-7y9z:
Cryo-EM structure of SARS-CoV-2 Omicron spike protein (S-6P-RRAR) in complex with human ACE2 ectodomain (one-RBD-up state)
Method: EM (single particle) / Resolution: 2.85 Å

EMDB-33698, PDB-7ya0:
Cryo-EM structure of hACE2-bound SARS-CoV-2 Omicron spike protein with L371S, P373S and F375S mutations (S-6P-RRAR)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-33699, PDB-7ya1:
Cryo-EM structure of hACE2-bound SARS-CoV-2 Omicron spike protein with L371S, P373S and F375S mutations (local refinement)
Method: EM (single particle) / Resolution: 3.11 Å

EMDB-33709, PDB-7yad:
Cryo-EM structure of S309-RBD-RBD-S309 in the S309-bound Omicron spike protein (local refinement)
Method: EM (single particle) / Resolution: 2.66 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ZN:
Unknown entry

Source
  • severe acute respiratory syndrome coronavirus 2
  • homo sapiens (human)
KeywordsVIRAL PROTEIN / SARS-CoV-2 / Omicron / spike protein / VIRAL PROTEIN/HYDROLASE / ACE2 / one RBD up / VIRUS / VIRAL PROTEIN-HYDROLASE complex / HYDROLASE/VIRAL PROTEIN / HYDROLASE-VIRAL PROTEIN complex / IMMUNE SYSTEM/VIRAL PROTEIN / S309 antibody / IMMUNE SYSTEM-VIRAL PROTEIN complex

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