Sophie M-C Gobeil / Katarzyna Janowska / Shana McDowell / Katayoun Mansouri / Robert Parks / Kartik Manne / Victoria Stalls / Megan F Kopp / Rory Henderson / Robert J Edwards / Barton F Haynes / Priyamvada Acharya /
PubMed Abstract
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, ...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.
EMDB-22821, PDB-7kdg: SARS-CoV-2 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS) Method: EM (single particle) / Resolution: 3.01 Å
EMDB-22822, PDB-7kdh: SARS-CoV-2 RBD up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS) Method: EM (single particle) / Resolution: 3.33 Å
EMDB-22823, PDB-7kdi: SARS-CoV-2 D614G 3 RBD down Spike Protein Trimer fully cleaved by furin without the P986-P987 stabilizing mutations (S-RRAR-D614G) Method: EM (single particle) / Resolution: 3.26 Å
EMDB-22824, PDB-7kdj: SARS-CoV-2 D614G 1-RBD-up Spike Protein Trimer fully cleaved by furin without the P986-P987 stabilizing mutations (S-RRAR-D614G) Method: EM (single particle) / Resolution: 3.49 Å
EMDB-22825, PDB-7kdk: SARS-CoV-2 D614G 3 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G) Method: EM (single particle) / Resolution: 2.8 Å
EMDB-22826, PDB-7kdl: SARS-CoV-2 D614G 1-RBD up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G) Method: EM (single particle) / Resolution: 2.96 Å
EMDB-22831, PDB-7ke4: SARS-CoV-2 D614G 3 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G Sub-class) Method: EM (single particle) / Resolution: 3.21 Å
EMDB-22832, PDB-7ke6: SARS-CoV-2 D614G 3 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G sub-classification) Method: EM (single particle) / Resolution: 3.1 Å
EMDB-22833, PDB-7ke7: SARS-CoV-2 D614G 3-RBD-down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G Sub-Classification) Method: EM (single particle) / Resolution: 3.32 Å
EMDB-22834, PDB-7ke8: SARS-CoV-2 D614G 3 RBD down Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G sub-classification) Method: EM (single particle) / Resolution: 3.26 Å
EMDB-22835, PDB-7ke9: SARS-CoV-2 D614G 1-RBD-up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G sub-classification) Method: EM (single particle) / Resolution: 3.08 Å
EMDB-22836, PDB-7kea: SARS-CoV-2 D614G 1-RBD-up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G sub classification) Method: EM (single particle) / Resolution: 3.33 Å
EMDB-22837, PDB-7keb: SARS-CoV-2 D614G 1RBD up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G sub-classification) Method: EM (single particle) / Resolution: 3.48 Å
EMDB-22838, PDB-7kec: SARS-CoV-2 D614G 1-RBD-up Spike Protein Trimer without the P986-P987 stabilizing mutations (S-GSAS-D614G Sub-Classification) Method: EM (single particle) / Resolution: 3.84 Å
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VIRAL PROTEIN / SARS-CoV-2 Spike Protein Trimer
