Dhiraj Mannar / James W Saville / Zehua Sun / Xing Zhu / Michelle M Marti / Shanti S Srivastava / Alison M Berezuk / Steven Zhou / Katharine S Tuttle / Michele D Sobolewski / Andrew Kim / Benjamin R Treat / Priscila Mayrelle Da Silva Castanha / Jana L Jacobs / Simon M Barratt-Boyes / John W Mellors / Dimiter S Dimitrov / Wei Li / Sriram Subramaniam /
PubMed Abstract
Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V ab6) that ...Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants.
EMDB-27503, PDB-8dlj: Cryo-EM structure of SARS-CoV-2 Alpha (B.1.1.7) spike protein in complex with human ACE2 Method: EM (single particle) / Resolution: 2.91 Å
EMDB-27504, PDB-8dlk: Cryo-EM structure of SARS-CoV-2 Alpha (B.1.1.7) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2) Method: EM (single particle) / Resolution: 3.04 Å
EMDB-27506, PDB-8dlm: Cryo-EM structure of SARS-CoV-2 Beta (B.1.351) spike protein in complex with human ACE2 Method: EM (single particle) / Resolution: 2.89 Å
EMDB-27507, PDB-8dln: Cryo-EM structure of SARS-CoV-2 Beta (B.1.351) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2) Method: EM (single particle) / Resolution: 3.04 Å
EMDB-27509, PDB-8dlp: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with human ACE2 Method: EM (single particle) / Resolution: 2.64 Å
EMDB-27510, PDB-8dlq: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2) Method: EM (single particle) / Resolution: 2.77 Å
EMDB-27511: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with Fab 4-8 Method: EM (single particle) / Resolution: 2.59 Å
EMDB-27512, PDB-8dlr: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with Fab 4-8 (focused refinement of NTD and 4-8) Method: EM (single particle) / Resolution: 2.51 Å
EMDB-27513: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with Fab 4A8 Method: EM (single particle) / Resolution: 2.59 Å
EMDB-27514, PDB-8dls: Cryo-EM structure of SARS-CoV-2 Gamma (P.1) spike protein in complex with Fab 4A8 (focused refinement of NTD and 4A8) Method: EM (single particle) / Resolution: 2.66 Å
EMDB-27516, PDB-8dlu: Cryo-EM structure of SARS-CoV-2 Epsilon (B.1.429) spike protein in complex with human ACE2 Method: EM (single particle) / Resolution: 3.14 Å
EMDB-27517, PDB-8dlv: Cryo-EM structure of SARS-CoV-2 Epsilon (B.1.429) spike protein in complex with human ACE2 (focused refinement of RBD and ACE2) Method: EM (single particle) / Resolution: 3.11 Å
EMDB-27518, PDB-8dlw: Cryo-EM structure of SARS-CoV-2 Epsilon (B.1.429) spike protein in complex with Fab S2M11 Method: EM (single particle) / Resolution: 2.16 Å
EMDB-27519, PDB-8dlx: Cryo-EM structure of SARS-CoV-2 Epsilon (B.1.429) spike protein in complex with VH ab6 Method: EM (single particle) / Resolution: 2.45 Å
EMDB-27520, PDB-8dly: Cryo-EM structure of SARS-CoV-2 Epsilon (B.1.429) spike protein in complex with VH ab6 (focused refinement of NTD and VH ab6) Method: EM (single particle) / Resolution: 3.0 Å
EMDB-27522, PDB-8dm0: Cryo-EM structure of SARS-CoV-2 D614G spike protein in complex with VH ab6 (focused refinement of NTD and VH ab6) Method: EM (single particle) / Resolution: 3.21 Å
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