摘要
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-2S-RBD bound to the ACE2 mutants reveal that the enhan ced binding is mainly con tributed by the van der Waals interactio ns mediated by the aromatic side-chai ns 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,explai ning their in compatibility.Finally,using pseudotyped SARS-CoV-2 viruses,we dem on strate 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 dinical treatment of COVID-19.
基金
supported by the special research fund on COVID-19 of Sichuan Province(Grant no.2020YFS0010)
the special research fund on COVID-19 of West China Hospital Sichuan University(Grant no.HX-2019-nCoV-004)
the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(Grant no.ZYYC20008).