2hats
Dust.
(UWash) A study of the electrostatic structure of omicron/B.1.1.529 when interacting with a key monoclonal antibody (sotrovimab family) and human ACE2 provides an explanation for the apparent behaviour of this variant. CryoEM and X-ray diffraction analysis were performed in order to understand the spike structure and electrostatic interactions at the molecular level.
This work reveals that the N-terminal domain has substantially changed structural arrangement, explaining the loss of binding and neutralisation by a wide range of monoclonal antibodies which target epitopes in this region. Additionally, key mutations in the S2 subunit (part of the fusion machinery) have increased electrostatic binding to the S1 subunit. This has three effects: (1) reduction in cleavage reducing fusogenicity, (2) increase in spike stability and binding sites (and thus viral infectivity, as seen in earlier studies) and (3) limiting S1 shedding which (other studies in animal models have suggested) may increase antibody Fc effector functions (ie pathways to cellular immune response). Finally, they find that K417N, S477N, Q493R, Q498R and N501Y collectively enhance ACE2 binding through the electrostatic changes that they bring about.
Like others, they also note the efficiency with which omicron RBD binds to murine ACE2.
DOI: 10.1101/2021.12.28.474380.
This work reveals that the N-terminal domain has substantially changed structural arrangement, explaining the loss of binding and neutralisation by a wide range of monoclonal antibodies which target epitopes in this region. Additionally, key mutations in the S2 subunit (part of the fusion machinery) have increased electrostatic binding to the S1 subunit. This has three effects: (1) reduction in cleavage reducing fusogenicity, (2) increase in spike stability and binding sites (and thus viral infectivity, as seen in earlier studies) and (3) limiting S1 shedding which (other studies in animal models have suggested) may increase antibody Fc effector functions (ie pathways to cellular immune response). Finally, they find that K417N, S477N, Q493R, Q498R and N501Y collectively enhance ACE2 binding through the electrostatic changes that they bring about.
Like others, they also note the efficiency with which omicron RBD binds to murine ACE2.
DOI: 10.1101/2021.12.28.474380.