Abstract
The recently reported “UK variant” (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments.
Highlights
The rapid international spread of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the causative agent of COVID-19, is associated with numerous mutations that alter viral fitness
A cryo-electron microscopy (cryo-EM) structure of the spike protein ectodomain with the N501Y mutation was obtained at an average resolution of approximately 2.8 Å (Table 1; S2 Fig)
The overall structure at the binding site is almost identical to that of the unmutated version (Fig 1D) [7], with the exception of local rearrangements that result in the aromatic ring of Y501 being accommodated in a cavity that is sandwiched between Y41 and K353 of the angiotensin converting enzyme 2 (ACE2) receptor (Fig 1E)
Summary
The rapid international spread of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the causative agent of COVID-19, is associated with numerous mutations that alter viral fitness. Mutations have been documented in all 4 structural proteins encoded by the viral genome including the small envelope glycoprotein (E), membrane glycoprotein (M), nucleocapsid (N) protein, and the spike (S) protein. The most prominent mutations are in the spike protein, which mediates entry of the virus into cells by engaging with the angiotensin converting enzyme 2 (ACE2) receptor. Several structures of SARS-CoV-2 spike protein variants in pre- and post-fusion conformations have been reported, including complexes with ACE2 and a variety of antibodies [1,2,3,4,5,6,7,8,9,10,11,12,13].
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