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TitleEffect of the S2' site cleavage on SARS-CoV-2 spike.
Journal, issue, pagesNat Commun, Year 2025
Publish dateNov 27, 2025
AuthorsWei Shi / G M Jonaid / Md Golam Kibria / Jacob Allen / Hanqin Peng / Sophia Rits-Volloch / Haisun Zhu / Shaowei Wang / Richard M Walsh / Jianming Lu / Bing Chen /
PubMed AbstractSARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds ...SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2' site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2' cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2' cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.
External linksNat Commun / PubMed:41309650
MethodsEM (single particle)
Resolution2.82 - 6.8 Å
Structure data

49912

9nxy

EMDB-49912, PDB-9nxy:
Cryo-EM structure of SARS-CoV-2 spike S2' trimer
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-49917: Cryo-EM structure of SARS-CoV-2 spike S2' trimer (local map 1)
Method: EM (single particle) / Resolution: 3.04 Å

EMDB-49918: Cryo-EM structure of SARS-CoV-2 spike S2' trimer (local map 2)
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-49921: Cryo-EM structure of SARS-CoV-2 spike S2' trimer (dimer of trimer)
Method: EM (single particle) / Resolution: 6.8 Å

Chemicals

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

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsVIRAL PROTEIN / SARS-CoV-2 / spike protein / postfusion / intermediate

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