Molecular insights into receptor binding of recent emerging SARS-CoV-2 variants

Pengcheng Han,Yanfang Zhang,Yuqin Zhang,Chao Su,Qing Wang,Jing Li,Jinghua Yan,Xin Zhao,Qian Chen,Hanyi Liao,Anqi Zheng,Qihui Wang,Yu Hu,Zengyuan Zhang,Moon-Sik Yang ,Xiaoyu Rong,Sheng Niu,Heecheol Cho,Niu Huang,Weiwei Li,Chengpeng Qiao,George F Gao ,C H Bai ,Jianxun Qi

doi:10.1038/s41467-021-26401-w

Abstract

Multiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. However, there is yet a lack of understanding of the molecular basis for the interactions between the human ACE2 (hACE2) receptor and these VOCs. Here we examined several VOCs including Alpha, Beta, and Gamma, and demonstrate that five variants receptor-binding domain (RBD) increased binding affinity for hACE2, and four variants pseudoviruses increased entry into susceptible cells. Crystal structures of hACE2-RBD complexes help identify the key residues facilitating changes in hACE2 binding affinity. Additionally, soluble hACE2 protein efficiently prevent most of the variants pseudoviruses. Our findings provide important molecular information and may help the development of novel therapeutic and prophylactic agents targeting these emerging mutants.

Highlights

Multiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally
The binding of receptor-binding domain (RBD) to the receptor human angiotensin-converting enzyme 2 (ACE2) (hACE2) is an essential step for virus to entry cell, we first explored if the binding of six SARS-CoV-2 variant RBDs to hACE2 were changed in comparison with wild-type (WT) SARSCoV-2 RBD
Mouse Fc tagged hACE2 was captured in a CM5 chip that pre-immobilized with anti-mFc antibody, and the serially diluted variant RBDs were flowed through the chip

Summary

Introduction

Multiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. Up-to date, tremendous efforts have led to the development of vaccine, combine with the preventive measures prescribed by the government around the world, the transmission of the virus among human are still going and numerous SARS-CoV-2 mutations with uncertain consequences for viral replication and transmission are being increasingly identified. The mutation of the spike (S) protein in SARS-CoV-2 has drawn wide concerns because S proteins mediate viral entry via their interaction with the angiotensin-converting enzyme 2 (ACE2) receptor[3,4] and are the major target for vaccine development. Several novel SARS-CoV-2 variants of concern (VOCs) carrying D614G mutation have been linked to an increased number of infections at a global scale VOC Gamma (P.1 lineage or 501Y.V3) is a novel lineage tracing back to the B.1.1.28 lineage and was found to be circulating in Manaus, Brazil, in December 2020, with this isolate being identified in 42% of the specimens sequenced from this region in mid/late December[10]

Methods

Results

Conclusion