D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction.

Journal Article (Journal Article)

The severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein is the target of vaccine design efforts to end the coronavirus disease 2019 (COVID-19) pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic and are now the dominant form worldwide. Here, we explore S conformational changes and the effects of the D614G mutation on a soluble S ectodomain construct. Cryoelectron microscopy (cryo-EM) structures reveal altered receptor binding domain (RBD) disposition; antigenicity and proteolysis experiments reveal structural changes and enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage alters the up/down ratio of the RBDs in the G614 S ectodomain, demonstrating an allosteric effect on RBD positioning triggered by changes in the SD2 region, which harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 S conformational landscape and allostery and have implications for vaccine design.

Full Text

Duke Authors

Cited Authors

  • Gobeil, SM-C; Janowska, K; McDowell, S; Mansouri, K; Parks, R; Manne, K; Stalls, V; Kopp, MF; Henderson, R; Edwards, RJ; Haynes, BF; Acharya, P

Published Date

  • January 12, 2021

Published In

Volume / Issue

  • 34 / 2

Start / End Page

  • 108630 -

PubMed ID

  • 33417835

Pubmed Central ID

  • PMC7762703

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2020.108630


  • eng

Conference Location

  • United States