Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Shihui Sun; Hongjing Gu; Lei Cao; Qi Chen; Qing Ye; Guan Yang; Rui Ting Li; Hang Fan; Yong Qiang Deng; Xiaopeng Song; Yini Qi; Min Li; Jun Lan; Rui Feng; Yan Guo; Na Zhu; Si Qin; Lei Wang; Yi Fei Zhang; Chao Zhou; Lingna Zhao; Yuehong Chen; Meng Shen; Yujun Cui; Xiao Yang; Xinquan Wang; Wenjie Tan; Hui Wang; Xiangxi Wang; Cheng Feng Qin

doi:10.1038/s41467-021-25903-x

Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Shihui Sun, Hongjing Gu, Lei Cao, Qi Chen, Qing Ye, Guan Yang, Rui Ting Li, Hang Fan, Yong Qiang Deng, Xiaopeng Song, Yini Qi, Min Li, Jun Lan, Rui Feng, Yan Guo, Na Zhu, Si Qin, Lei Wang, Yi Fei Zhang, Chao ZhouLingna Zhao, Yuehong Chen, Meng Shen, Yujun Cui, Xiao Yang, Xinquan Wang, Wenjie Tan, Hui Wang, Xiangxi Wang, Cheng Feng Qin

Research output: Contribution to journal › Article › peer-review

73 Scopus citations

Abstract

There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.

Original language	English
Article number	5654
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-25903-x
State	Published - 1 Dec 2021
Externally published	Yes

Access to Document

10.1038/s41467-021-25903-x

Cite this

@article{2d3ca1765e104921891e3cdc66ee6f68,

title = "Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2",

abstract = "There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 {\AA} resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.",

author = "Shihui Sun and Hongjing Gu and Lei Cao and Qi Chen and Qing Ye and Guan Yang and Li, \{Rui Ting\} and Hang Fan and Deng, \{Yong Qiang\} and Xiaopeng Song and Yini Qi and Min Li and Jun Lan and Rui Feng and Yan Guo and Na Zhu and Si Qin and Lei Wang and Zhang, \{Yi Fei\} and Chao Zhou and Lingna Zhao and Yuehong Chen and Meng Shen and Yujun Cui and Xiao Yang and Xinquan Wang and Wenjie Tan and Hui Wang and Xiangxi Wang and Qin, \{Cheng Feng\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-25903-x",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Sun, S, Gu, H, Cao, L, Chen, Q, Ye, Q, Yang, G, Li, RT, Fan, H, Deng, YQ, Song, X, Qi, Y, Li, M, Lan, J, Feng, R, Guo, Y, Zhu, N, Qin, S, Wang, L, Zhang, YF, Zhou, C, Zhao, L, Chen, Y, Shen, M, Cui, Y, Yang, X, Wang, X, Tan, W, Wang, H, Wang, X & Qin, CF 2021, 'Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2', Nature Communications, vol. 12, no. 1, 5654. https://doi.org/10.1038/s41467-021-25903-x

TY - JOUR

T1 - Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

AU - Sun, Shihui

AU - Gu, Hongjing

AU - Cao, Lei

AU - Chen, Qi

AU - Ye, Qing

AU - Yang, Guan

AU - Li, Rui Ting

AU - Fan, Hang

AU - Deng, Yong Qiang

AU - Song, Xiaopeng

AU - Qi, Yini

AU - Li, Min

AU - Lan, Jun

AU - Feng, Rui

AU - Guo, Yan

AU - Zhu, Na

AU - Qin, Si

AU - Wang, Lei

AU - Zhang, Yi Fei

AU - Zhou, Chao

AU - Zhao, Lingna

AU - Chen, Yuehong

AU - Shen, Meng

AU - Cui, Yujun

AU - Yang, Xiao

AU - Wang, Xinquan

AU - Tan, Wenjie

AU - Wang, Hui

AU - Wang, Xiangxi

AU - Qin, Cheng Feng

PY - 2021/12/1

Y1 - 2021/12/1

N2 - There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.

AB - There is an urgent need for animal models to study SARS-CoV-2 pathogenicity. Here, we generate and characterize a novel mouse-adapted SARS-CoV-2 strain, MASCp36, that causes severe respiratory symptoms, and mortality. Our model exhibits age- and gender-related mortality akin to severe COVID-19. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three RBD mutations significantly enhance binding affinity to its endogenous receptor, ACE2. Cryo-electron microscopy analysis of human ACE2 (hACE2), or mouse ACE2 (mACE2), in complex with the RBD of MASCp36, at 3.1 to 3.7 Å resolution, reveals the molecular basis for the receptor-binding switch. N501Y and Q493H enhance the binding affinity to hACE2, whereas triple mutations at N501Y/Q493H/K417N decrease affinity and reduce infectivity of MASCp36. Our study provides a platform for studying SARS-CoV-2 pathogenesis, and unveils the molecular mechanism for its rapid adaptation and evolution.

UR - https://www.scopus.com/pages/publications/85115773072

U2 - 10.1038/s41467-021-25903-x

DO - 10.1038/s41467-021-25903-x

M3 - Article

C2 - 34580297

AN - SCOPUS:85115773072

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5654

ER -

Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

Abstract

Access to Document

Fingerprint

Cite this