7ZDQ

Cryo-EM structure of Human ACE2 bound to a high-affinity SARS CoV-2 mutant

Summary for 7ZDQ

• Entry DOI: 10.2210/pdb7zdq/pdb
• EMDB information: 14666
• Descriptor: Processed angiotensin-converting enzyme 2, Spike protein S1, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: sars cov-2, rbd, ace2, viral protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 100053.85

Authors

Bate, N.,Savva, C.G.,Moody, P.C.E.,Brown, E.A.,Schwabe, W.R.,Brindle, N.P.J.,Ball, J.K.,Sale, J.E. (deposition date: 2022-03-29, release date: 2022-05-18, Last modification date: 2022-08-10)

Primary citation

Bate, N.,Savva, C.G.,Moody, P.C.E.,Brown, E.A.,Evans, S.E.,Ball, J.K.,Schwabe, J.W.R.,Sale, J.E.,Brindle, N.P.J.
In vitro evolution predicts emerging SARS-CoV-2 mutations with high affinity for ACE2 and cross-species binding.
Plos Pathog., 18:e1010733-e1010733, 2022

PubMed 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.

PubMed: 35849637
DOI: 10.1371/journal.ppat.1010733

Experimental method

ELECTRON MICROSCOPY (3.2 Å)