7EFR

Structure of SARS-CoV-2 spike receptor-binding domain in complex with high affinity ACE2 mutant (T27W,N330Y)

Summary for 7EFR

• Entry DOI: 10.2210/pdb7efr/pdb
• Descriptor: Processed angiotensin-converting enzyme 2, Spike glycoprotein, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: receptor-binding domain, angiotensin converting enzyme 2, viral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 94982.52

Authors

Lu, G.W.,Ye, F.,Lin, X. (deposition date: 2021-03-23, release date: 2021-11-24, Last modification date: 2024-10-16)

Primary citation

Ye, F.,Lin, X.,Chen, Z.,Yang, F.,Lin, S.,Yang, J.,Chen, H.,Sun, H.,Wang, L.,Wen, A.,Zhang, X.,Dai, Y.,Cao, Y.,Yang, J.,Shen, G.,Yang, L.,Li, J.,Wang, Z.,Wang, W.,Wei, X.,Lu, G.
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.
Signal Transduct Target Ther, 6:343-343, 2021

PubMed Abstract: 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.

PubMed: 34531369
DOI: 10.1038/s41392-021-00756-4

Experimental method

X-RAY DIFFRACTION (2.494 Å)