Sophie M-C Gobeil / Katarzyna Janowska / Shana McDowell / Katayoun Mansouri / Robert Parks / Victoria Stalls / Megan F Kopp / Kartik Manne / Dapeng Li / Kevin Wiehe / Kevin O Saunders / Robert J Edwards / Bette Korber / Barton F Haynes / Rory Henderson / Priyamvada Acharya /
PubMed Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo-electron microscopy (cryo- ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo-electron microscopy (cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)-up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization.
EMDB-23546, PDB-7lwi: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 3-RBD down conformation Method: EM (single particle) / Resolution: 3.07 Å
EMDB-23547, PDB-7lwj: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 3-RBD down conformation Method: EM (single particle) / Resolution: 3.24 Å
EMDB-23548, PDB-7lwk: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 3-RBD down conformation Method: EM (single particle) / Resolution: 2.92 Å
EMDB-23549, PDB-7lwl: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 3-RBD down conformation Method: EM (single particle) / Resolution: 2.84 Å
EMDB-23550, PDB-7lwm: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 1-RBD up conformation Method: EM (single particle) / Resolution: 2.83 Å
EMDB-23551, PDB-7lwn: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 1-RBD up conformation Method: EM (single particle) / Resolution: 2.94 Å
EMDB-23552, PDB-7lwo: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 1-RBD up conformation Method: EM (single particle) / Resolution: 2.85 Å
EMDB-23553, PDB-7lwp: Mink Cluster 5-associated SARS-CoV-2 spike protein (S-GSAS-D614G-delFV) in the 2-RBD up conformation Method: EM (single particle) / Resolution: 3.01 Å
EMDB-23554, PDB-7lwq: Mink Cluster 5-associated SARS-CoV-2 spike protein(S-GSAS-D614G-delFV) missing the S1 subunit and SD2 subdomain of one protomer Method: EM (single particle) / Resolution: 3.44 Å
EMDB-23556, PDB-7lwt: UK (B.1.1.7) SARS-CoV-2 spike protein variant (S-GSAS-B.1.1.7) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.19 Å
EMDB-23557, PDB-7lwu: UK (B.1.1.7) SARS-CoV-2 spike protein variant (S-GSAS-B.1.1.7) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.22 Å
EMDB-23558, PDB-7lwv: UK (B.1.1.7) SARS-CoV-2 spike protein variant (S-GSAS-B.1.1.7) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.12 Å
EMDB-23559, PDB-7lww: Triple mutant (K417N-E484K-N501Y) SARS-CoV-2 spike protein in the 1-RBD-up conformation (S-GSAS-D614G-K417N-E484K-N501Y) Method: EM (single particle) / Resolution: 3.0 Å
EMDB-23593, PDB-7lyk: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the 2-RBD-up conformation Method: EM (single particle) / Resolution: 3.65 Å
EMDB-23594, PDB-7lyl: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the RBD-down conformation Method: EM (single particle) / Resolution: 3.72 Å
EMDB-23595, PDB-7lym: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the RBD-down conformation Method: EM (single particle) / Resolution: 3.57 Å
EMDB-23596, PDB-7lyn: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.32 Å
EMDB-23597, PDB-7lyo: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.32 Å
EMDB-23598, PDB-7lyp: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 4.05 Å
EMDB-23599, PDB-7lyq: South African (B.1.351) SARS-CoV-2 spike protein variant (S-GSAS-B.1.351) in the 1-RBD-up conformation Method: EM (single particle) / Resolution: 3.34 Å
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Keywords
severe acute respiratory syndrome coronavirus 2