In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 7 ( 2022-7-18), p. e1010733-
Abstract:
Emerging SARS-CoV-2 variants are creating major challenges in the ongoing COVID-19 pandemic. Being able to predict mutations that could arise in SARS-CoV-2 leading to increased transmissibility or immune evasion would be extremely valuable in development of broad-acting therapeutics and vaccines, and prioritising viral monitoring and containment. Here we use in vitro evolution to seek mutations in SARS-CoV-2 receptor binding domain (RBD) that would substantially increase binding to ACE2. We find a double mutation, S477N and Q498H, that increases affinity of RBD for ACE2 by 6.5-fold. This affinity gain is largely driven by the Q498H mutation. We determine the structure of the mutant-RBD:ACE2 complex by cryo-electron microscopy to reveal the mechanism for increased affinity. Addition of Q498H to SARS-CoV-2 RBD variants is found to boost binding affinity of the variants for human ACE2 and confer a new ability to bind rat ACE2 with high affinity. Surprisingly however, in the presence of the common N501Y mutation, Q498H inhibits binding, due to a clash between H498 and Y501 side chains. To achieve an intermolecular bonding network, affinity gain and cross-species binding similar to Q498H alone, RBD variants with the N501Y mutation must acquire instead the related Q498R mutation. Thus, SARS-CoV-2 RBD can access large affinity gains and cross-species binding via two alternative mutational routes involving Q498, with route selection determined by whether a variant already has the N501Y mutation. These mutations are now appearing in emerging SARS-CoV-2 variants where they have the potential to influence human-to-human and cross-species transmission.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010733
DOI:
10.1371/journal.ppat.1010733.g001
DOI:
10.1371/journal.ppat.1010733.g002
DOI:
10.1371/journal.ppat.1010733.g003
DOI:
10.1371/journal.ppat.1010733.g004
DOI:
10.1371/journal.ppat.1010733.g005
DOI:
10.1371/journal.ppat.1010733.t001
DOI:
10.1371/journal.ppat.1010733.s001
DOI:
10.1371/journal.ppat.1010733.s002
DOI:
10.1371/journal.ppat.1010733.s003
DOI:
10.1371/journal.ppat.1010733.s004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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