The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses

Junsen Chen; Junqing Sun; Zepeng Xu; Linjie Li; Xinrui Kang; Chunliang Luo; Qi Wang; Xueyang Guo; Yan Li; Kefang Liu; Ying Wu

doi:10.1016/j.virs.2024.06.004

August 2024

Junsen Chen, Junqing Sun, Zepeng Xu, Linjie Li, Xinrui Kang, Chunliang Luo, Qi Wang, Xueyang Guo, Yan Li, Kefang Liu and Ying Wu. The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses[J]. Virologica Sinica, 2024, 39(4): 609-618. doi: 10.1016/j.virs.2024.06.004

Citation: Junsen Chen, Junqing Sun, Zepeng Xu, Linjie Li, Xinrui Kang, Chunliang Luo, Qi Wang, Xueyang Guo, Yan Li, Kefang Liu, Ying Wu. The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses .VIROLOGICA SINICA, 2024, 39(4) : 609-618. http://dx.doi.org/10.1016/j.virs.2024.06.004

不同沙贝病毒RBD与狐狸ACE2的受体结合及分子机制

陈俊森 ^a ,
孙俊清 ^b,c ,
徐泽鹏 ^b,d ,
李霖杰 ^b ,
康新锐 ^b ,
Chunliang Luo ^b ,
汪琪 ^a ,
郭雪洋 ^a ,
李燕 ^b ,
刘科芳 ^c,, ,
吴莹 ^a,,

cstr: 32224.14.j.virs.2024.06.004

a. 武汉大学泰康医学院(基础医学院)医学病毒学研究所病毒学国家重点实验室、过敏与免疫学湖北省重点实验室;
b. 中国科学院微生物研究所中国科学院病原微生物学与免疫学重点实验室;
c. 北京生命科技研究院;
d. 澳门大学健康科学学院

通讯作者： 刘科芳, liukf@im.ac.cn; 吴莹, yingwu@whu.edu.cn
收稿日期： 2024-03-19
录用日期： 2024-06-06

摘要

研究发现狐狸具备自然感染SARS-CoV和SARS-CoV-2的能力，实验室攻毒实验也证明狐狸可以感染SARS-CoV-2。本研究评估了狐狸ACE2与SARS-CoV、SARS-CoV-2和动物源性冠状病毒等重要的沙贝病毒（sarbecoviruses）的受体结合区（RBD）的结合能力。本研究结果表明，狐狸ACE2与检测的沙贝病毒RBD均能够结合，但亲和力有所差异。通过冷冻电镜技术解析了狐狸ACE2与SARS-CoV、SARS-CoV-2 原型和Omicron BF.7的RBD的复合物结构。通过结构分析，我们发现K417突变削弱SARS-CoV-2 RBD与狐狸ACE2的结合能力。此外，SARS-CoV RBD中的Y498残基在形成与狐狸ACE2受体的关键阳离子-π相互作用中发挥着至关重要的作用。与SARS-CoV-2原型RBD相比，这种相互作用是狐狸ACE2与SARS-CoV RBD亲和力更高的主要决定因素。这些结果进一步阐释了冠状病毒跨种识别的分子机制，提示狐狸可能是多种沙贝病毒的潜在宿主，需加强对狐狸携带冠状病毒的监测，以防病毒外溢，引起新的大流行。
- 沙贝病毒
- , SARS-CoV
- , SARS-CoV-2
- , 狐狸ACE2
- , 奥密克隆
- , 冷冻电镜结构

The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses

Junsen Chen ^a ,
Junqing Sun ^b,c ,
Zepeng Xu ^b,d ,
Linjie Li ^b ,
Xinrui Kang ^b ,
Chunliang Luo ^b ,
Qi Wang ^a ,
Xueyang Guo ^a ,
Yan Li ^b ,
Kefang Liu ^c,, ,
Ying Wu ^a,,

a. State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China;
b. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China;
c. Beijing Life Science Academy, Beijing, 102209, China;
d. Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, China

Corresponding author: Kefang Liu, liukf@im.ac.cn Ying Wu, yingwu@whu.edu.cn
Received Date: 19 March 2024
Accepted Date: 06 June 2024

Abstract

Foxes are susceptible to SARS-CoV-2 in laboratory settings, and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes. In this study, we assessed the binding capacities of fox ACE2 to important sarbecoviruses, including SARS-CoV, SARS-CoV-2, and animal-origin SARS-CoV-2 related viruses. Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains (RBDs) of sarbecoviruses. We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV, SARS-CoV-2 prototype (PT), and Omicron BF.7. Through structural analysis, we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2, thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants. In addition, the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-π interaction with K353 in the fox ACE2 receptor. This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD. These results indicate that foxes serve as potential hosts for numerous sarbecoviruses, highlighting the critical importance of surveillance efforts.
- Sarbecoviruses
- , SARS-CoV
- , SARS-CoV-2
- , Fox ACE2
- , Omicron
- , Cryo-EM structure

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10.1016j.virs.2024.06.004-ESM.docx