Molecular Basis of Mink ACE2 Binding to SARS-CoV-2 and Its Mink-Derived Variants
Chao Su, Juanhua He, Pengcheng Han, Bin Bai, Dedong Li, Jian Cao, Mingxiong Tian, Yu Hu, Anqi Zheng, Sheng Niu, Qian Chen, Xiaoyu Rong, Yanfang Zhang, Weiwei Li, Jianxun Qi, Xin Zhao, Mengsu Yang, Qihui Wang, George F. Gao
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a broad range of hosts. Mink-derived SARS-CoV-2 can transmit back to humans. There is an urgent need to understand the binding mechanism of mink-derived SARS-CoV-2 variants to mink receptor. In this study, we identified all mutations in the receptor-binding domain (RBD) of spike (S) protein from mink-derived SARS-CoV-2, and we demonstrated the enhanced binding affinity of mink angiotensin-converting enzyme 2 (ACE2) to most of the mink-derived RBD variants as well as important human-originating RBD variants. Cryo-electron microscopy structures revealed that the Y453F and F486L mutations enhanced the binding forces in the interaction interface. In addition, Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and the SARS-CoV-2 pseudoviruses with Y453F, F486L, or N501T mutations were neutralized by human vaccinated sera. Therefore, our results provide valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.