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TitleCryo-EM structures of alphavirus conformational intermediates in low pH-triggered prefusion states.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 30, Page e2114119119, Year 2022
Publish dateJul 26, 2022
AuthorsChun-Liang Chen / Thomas Klose / Chengqun Sun / Arthur S Kim / Geeta Buda / Michael G Rossmann / Michael S Diamond / William B Klimstra / Richard J Kuhn /
PubMed AbstractAlphaviruses can cause severe human arthritis and encephalitis. During virus infection, structural changes of viral glycoproteins in the acidified endosome trigger virus-host membrane fusion for ...Alphaviruses can cause severe human arthritis and encephalitis. During virus infection, structural changes of viral glycoproteins in the acidified endosome trigger virus-host membrane fusion for delivery of the capsid core and RNA genome into the cytosol to initiate virus translation and replication. However, mechanisms by which E1 and E2 glycoproteins rearrange in this process remain unknown. Here, we investigate prefusion cryoelectron microscopy (cryo-EM) structures of eastern equine encephalitis virus (EEEV) under acidic conditions. With models fitted into the low-pH cryo-EM maps, we suggest that E2 dissociates from E1, accompanied by a rotation (∼60°) of the E2-B domain (E2-B) to expose E1 fusion loops. Cryo-EM reconstructions of EEEV bound to a protective antibody at acidic and neutral pH suggest that stabilization of E2-B prevents dissociation of E2 from E1. These findings reveal conformational changes of the glycoprotein spikes in the acidified host endosome. Stabilization of E2-B may provide a strategy for antiviral agent development.
External linksProc Natl Acad Sci U S A / PubMed:35867819 / PubMed Central
MethodsEM (single particle)
Resolution5.1 - 18.2 Å
Structure data

EMDB-24199: Localized reconstruction of EEEV
Method: EM (single particle) / Resolution: 5.1 Å

EMDB-24200: Pre-fusion state 2 of EEEV
Method: EM (single particle) / Resolution: 16.4 Å

24201

7n69

EMDB-24201, PDB-7n69:
Pre-fusion state 2 of EEEV with localized reconstruction
Method: EM (single particle) / Resolution: 14.1 Å

EMDB-24202: EEEV in complex with Fab22 at acidic pH (pH 5.5)
Method: EM (single particle) / Resolution: 8.1 Å

EMDB-24203: EEEV in complex with Fab22 at neutral pH (pH 7.4)
Method: EM (single particle) / Resolution: 6.7 Å

EMDB-24204: Pre-fusion state 1 of EEEV
Method: EM (single particle) / Resolution: 18.2 Å

24205

7n6a

EMDB-24205, PDB-7n6a:
Pre-fusion state 1 of EEEV with localized reconstruction
Method: EM (single particle) / Resolution: 14.3 Å

Source
  • eastern equine encephalitis virus (strain florida 91-469)
KeywordsVIRUS / EEEV / pre-fusion / localized reconstruction

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