SARS-CoV-2 recognizes, via its spike receptor-binding domain (S-RBD), human angiotensin-converting enzyme 2 (ACE2) to initiate infection. Ecto-domain protein of ACE2 can therefore function as a decoy. Here we show that mutations of S19W, T27W, and N330Y in ACE2 could individually enhance SARS-CoV-2 S-RBD binding. Y330 could be synergistically combined with either W19 or W27, whereas W19 and W27 are mutually unbeneficial. The structures of SARS-CoV-2 S-RBD bound to the ACE2 mutants reveal that the enhanced binding is mainly contributed by the van der Waals interactions mediated by the aromatic side-chains from W19, W27, and Y330. While Y330 and W19/W27 are distantly located and devoid of any steric interference, W19 and W27 are shown to orient their side-chains toward each other and to cause steric conflicts, explaining their incompatibility. Finally, using pseudotyped SARS-CoV-2 viruses, we demonstrate that these residue substitutions are associated with dramatically improved entry-inhibition efficacy toward both wild-type and antibody-resistant viruses. Taken together, our biochemical and structural data have delineated the basis for the elevated S-RBD binding associated with S19W, T27W, and N330Y mutations in ACE2, paving the way for potential application of these mutants in clinical treatment of COVID-19.
【저자키워드】 Molecular biology, structural biology, 【초록키워드】 COVID-19, viruses, Structure, SARS-CoV-2, Efficacy, ACE2, Mutation, Infection, Protein, S-RBD, spike receptor-binding domain, mutant, binding, Human angiotensin-converting enzyme 2, Interaction, angiotensin, structures, Clinical treatment, decoy, biochemical, residue, human Angiotensin-converting enzyme, RBD binding, Substitution, wild-type, clinical treatment of COVID-19, van der Waals interactions, while, pseudotyped SARS-CoV-2, ENhance, shown, elevated, contributed, steric, van der Waal, 【제목키워드】 SARS-CoV-2, ACE2, Mutation, virus, binding, molecular basis, wild-type, ENhance,