Volume 6 Issue 10, Oct 2021:
Article
S19W, T27W, and N330Y mutations in ACE2 enhance SARS-CoV-2 S-RBD binding toward both wild-type and antibody-resistant viruses and its molecular basis
Fei Ye,Xi Lin,Zimin Chen,Fanli Yang,Sheng Lin,Jing Yang,Hua Chen,Honglu Sun,Lingling Wang,Ao Wen,Xindan Zhang,Yushan Dai,Yu Cao,Jingyun Yang,Guobo Shen,Li Yang,Jiong Li,Zhenling Wang,Wei Wang
ORCID: orcid.org/0000-0001-7788-1895,Xiawei Wei
ORCID: orcid.org/0000-0002-6513-6422 &…Guangwen Lu
ORCID: orcid.org/0000-0001-7568-592X
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.
