Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

doi:10.1016/j.cell.2020.03.045

. 2020 May 14;181(4):894-904.e9.

doi: 10.1016/j.cell.2020.03.045. Epub 2020 Apr 9.

Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

Qihui Wang¹, Yanfang Zhang², Lili Wu³, Sheng Niu⁴, Chunli Song⁵, Zengyuan Zhang⁶, Guangwen Lu⁷, Chengpeng Qiao⁸, Yu Hu⁹, Kwok-Yung Yuen¹⁰, Qisheng Wang¹¹, Huan Zhou¹¹, Jinghua Yan¹², Jianxun Qi¹³

Affiliations

¹ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Biotechnology, Tianjin 300308, China.
³ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
⁴ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu 030801, China.
⁵ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Institute of Physical Science and Information, Anhui University, Hefei 230039, China.
⁶ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
⁷ West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
⁸ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
¹⁰ State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China; Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
¹¹ Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
¹² CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Institute of Physical Science and Information, Anhui University, Hefei 230039, China; College of Life Science, University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: yanjh@im.ac.cn.
¹³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jxqi@im.ac.cn.

PMID: 32275855
PMCID: PMC7144619
DOI: 10.1016/j.cell.2020.03.045

Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

Qihui Wang et al. Cell. 2020.

. 2020 May 14;181(4):894-904.e9.

doi: 10.1016/j.cell.2020.03.045. Epub 2020 Apr 9.

Authors

Affiliations

¹ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
² CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Biotechnology, Tianjin 300308, China.
³ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
⁴ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu 030801, China.
⁵ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Institute of Physical Science and Information, Anhui University, Hefei 230039, China.
⁶ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
⁷ West China Hospital Emergency Department (WCHED), State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.
⁸ CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
⁹ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China.
¹⁰ State Key Laboratory for Emerging Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China; Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China.
¹¹ Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
¹² CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People's Hospital, Shenzhen 518112, China; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Institute of Physical Science and Information, Anhui University, Hefei 230039, China; College of Life Science, University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: yanjh@im.ac.cn.
¹³ CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of the Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jxqi@im.ac.cn.

PMID: 32275855
PMCID: PMC7144619
DOI: 10.1016/j.cell.2020.03.045

Abstract

The recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.

Keywords: ACE2; CTD; SARS-CoV-2; crystal structure; immunogenicity; receptor; receptor binding domain.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1**
SARS-CoV-2-S1 and SARS-CoV-2-CTD Co-localize with hACE2 HEK293T cells were transfected with pEGFP-N1-hACE2 (left panels, hACE2-GFP) or pEGFP-C1-hCD26 (right panels, hCD26-GFP). Twenty-four hours later, the cells were incubated with supernatant containing mFc-tagged SARS-CoV-2-S1 (SARS-CoV-2-S1-mFc), SARS-CoV-2-NTD (SARS-CoV-2-NTD-mFc), SARS-CoV-2-CTD (SARS-CoV-2-CTD-mFc), MERS-RBD (MERS-RBD-mFc), or SARS-RBD (SARS-RBD-mFc) proteins and subsequently incubated with anti-mouse IgG (mIgG) antibody conjugated with A594 (anti-mIgG/A594). Nuclei were stained with DAPI. All images were obtained by confocal microscopy using a Leica SP8 (×100 oil immersion objective lens). The scale bar in each panel indicates 8 μm. The data shown are representative of two independent experiments. See also Figure S2.

**Figure S2**
Characterization of Binding between SARS-CoV-2 and hACE2 by Flow Cytometry, Related to Figures 1 and 2 (A-C) Supernatant containing the indicated mFc-fusion proteins were incubated with HEK293T cells transiently expressing eGFP-tagged hACE2 (A), hCD26 (B) or hAPN (C), respectively. Anti-mIgG/APC was used to detect the mFc-fusion protein binding to the cells. Culture supernatant of HEK239T cells was used as negative control and marked as NC. For each sample, eGFP positive cells were first gated and then used to analyze fluorescence intensity of APC. (D-F) Supernatant containing SARS-CoV-2-CTD-mFc proteins were pre-incubated with soluble hACE2 (D), hCD26 (E) or hAPC (F) at the indicated concentrations before addition to HEK293T cells transfected with pEGFP-N1-hACE2. mFc-fusion protein binding to HEK293T cells were detected by anti-mIgG/APC. (G-I) Supernatant containing SARS-RBD-mFc proteins were pre-incubated with soluble hACE2 (G), hCD26 (H) or hAPC (I) at the indicated concentrations before addition to HEK293T cells transfected with pEGFP-N1-hACE2. mFc-fusion protein binding to HEK293T cells were detected by anti-mIgG/APC. (J-K) HEK293T cells transfected with pEGFP-N1-hACE2 were pre-incubated with soluble SARS-RBD at the indicated concentration, before the addition of supernatant containing either SARS-CoV-2-CTD-mFc (J) or SARS-RBD-mFc (K). mFc-fusion protein binding to HEK293T cells were detected by anti-mIgG/APC. (L-M) HEK293T cells transfected with pEGFP-N1-hACE2 (WT), or the mutants containing K353A (K353A) or K31A (K31A) were incubated with supernatant containing either SARS-CoV-2-CTD-mFc (L) or SARS-RBD-mFc (M). mFc-fusion protein binding to HEK293T cells were detected by anti-mIgG/APC. All data shown are representative of two independent experiments. The fluorescence signals were monitored by BD FACSCanto and the results were analyzed using FlowJo V10 (https://www.flowjo.com/solutions/flowjo/downloads).

**Figure 2**
The Complex Structure of SARS-CoV-2-CTD Bound to hACE2 (A) A cartoon representation of the complex structure. The core subdomain and external subdomain in SARS-CoV-2-CTD are colored cyan and orange, respectively. hACE2 subdomain I and II are colored violet and green, respectively. The right panel was obtained by anticlockwise rotation of the left panel along a longitudinal axis. The contacting sites are further delineated in (C)–(E) for the amino acid interaction details. (B) A carton representation of the SARS-CoV-2-CTD structure. The secondary structural elements are labeled according to their occurrence in sequence and location in the subdomains. Specifically, the β strands constituting the core subdomain are labeled with an extra c, whereas the elements in the external subdomain are labeled with an extra prime symbol. The disulfide bonds and N-glycan linked to N343 are shown as sticks and spheres, respectively. (C–E) Key contact sites are marked with the left, middle and right box in (A) and further delineated for interaction details, respectively. The residues involved are shown and labeled. See also Figures S1, S2, and S3 and Table S1.

**Figure S3**
Representative Electron Density Maps at the Binding Interface, Related to Figure 2 The electron densities of residues at the interaction interface between SARS-CoV-2-CTD and hACE2. The density maps are drawn in gray mesh contoured at 1 sigma. The core and external subdomains are colored cyan and orange, respectively. hACE2 is marked in violet. Residues in hACE2 that interact with the SARS-CoV-2-CTD are highlighted in lemon.

**Figure 3**
Comparison of the SARS-CoV-2-CTD/hACE2 and SARS-RBD/hACE2 Binding Sites (A) Overall similar receptor binding modes were observed for SARS-CoV-2-CTD and SARS-RBD. Superimposition of the structure of SARS-CoV-2-CTD (external subdomain in orange and core subdomain in cyan) bound to hACE2 (violet) and a complex structure of SARS-RBD (in gray) with hACE2 (yellow) are shown. The loop exhibiting variant conformations is highlighted by a dashed oval. (B) hACE2 displayed in surface view. Residues that interact with the SARS-CoV-2-CTD are marked. (C) hACE2 displayed in surface view. Residues that interact with the SARS-RBD are marked. (D) Residues substitutions in SARS-CoV-2-CTD slightly strengthen the interaction with the receptor compared to the SARS-RBD. The amino acid sequences of the loop specified in (A) were aligned between the SARS-CoV-2-CTD and the SARS-RBD. The numbers show the vdw contacts between the receptor with the indicated SARS-CoV-2-CTD residues (above the sequence) or SARS-RBD residues (below the sequence). Numbers in parentheses indicate the number of potential H-bonds conferred by the indicated residues. The red and blue arrows represent the amino acids that form ionic and aromatic-aromatic interactions with the receptor, respectively. See also Figure S1 and Table S1.

**Figure 4**
Specific Interactions between SARS-CoV-2-S1 and SARS-CoV-2-CTD with hACE2, Characterized by SPR The indicated mFc-tagged proteins in the supernatant were captured by anti-mIgG antibodies that were immobilized on the chip and subsequently tested for binding with gradient concentrations of hACE2 or hCD26, with the following binding profiles shown. (A) SARS-RBD binding to hACE2. (B) SARS-RBD binding to hCD26. (C) MERS-RBD binding to hACE2. (D) MERS-RBD binding to hCD26. (E) SARS-CoV-2-S1 binding to hACE2. (F) SARS-CoV-2-S1 binding to hCD26. (G) SARS-CoV-2-NTD binding to hACE2. (H) SARS-CoV-2-NTD binding to hCD26. (I) SARS-CoV-2-CTD binding to hACE2. (J) SARS-CoV-2-CTD binding to hCD26. (K) Culture supernatant of HEK293T cells without transfection (NC) binding to hACE2. (L) Culture supernatant of HEK293T cells without transfection (NC) binding to hCD26. The values shown are the mean ± SD of three independent experiments.

**Figure 5**
Different Antigenicity between the SARS-CoV-2 S and SARS-CoV S Proteins (A and B) HEK293T cells were transfected with pCAGGS plasmids containing Flag-tagged SARS-CoV S (A) or SARS-CoV-2 S (B). The indicated purified murine mAbs were subsequently added to the transfected cells before they were fixed, permeabilized, and stained with anti-Flag/fluorescein isothiocyanate (FITC). (C and D) HEK293T cells were transfected with pCAGGS plasmids expressing Flag-tagged SARS-CoV S. The murine polyclonal sera against SARS-RBD (C) or MERS-RBD (D) were subsequently added to the transfected cells before they were fixed, permeabilized, and stained with anti-Flag/FITC. (E and F) HEK293T cells were transfected with pCAGGS plasmids expressing Flag-tagged SARS-CoV-2 S. The murine polyclonal sera against SARS-RBD (E) or MERS-RBD (F) were subsequently added to the transfected cells before they were fixed, permeabilized, and stained with anti-Flag/FITC. (G) Electrostatic surface view of SARS-CoV-2-CTD. The first panel represents the top view. The others are yielded by rotation of the former panel along a horizontal axis. (H) Electrostatic surface view of SARS-RBD. The first panel represents the top view. The others are yielded by rotation of the former panel along a horizontal axis.

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References

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[1] Adams P.D., Afonine P.V., Bunkóczi G., Chen V.B., Davis I.W., Echols N., Headd J.J., Hung L.W., Kapral G.J., Grosse-Kunstleve R.W. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 2010;66:213–221. - PMC - PubMed

[2] Adams P.D., Afonine P.V., Bunkóczi G., Chen V.B., Davis I.W., Echols N., Headd J.J., Hung L.W., Kapral G.J., Grosse-Kunstleve R.W. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 2010;66:213–221. - PMC - PubMed

[3] Azhar E.I., El-Kafrawy S.A., Farraj S.A., Hassan A.M., Al-Saeed M.S., Hashem A.M., Madani T.A. Evidence for camel-to-human transmission of MERS coronavirus. N. Engl. J. Med. 2014;370:2499–2505. - PubMed

[4] Azhar E.I., El-Kafrawy S.A., Farraj S.A., Hassan A.M., Al-Saeed M.S., Hashem A.M., Madani T.A. Evidence for camel-to-human transmission of MERS coronavirus. N. Engl. J. Med. 2014;370:2499–2505. - PubMed

[5] Chiu S.S., Chan K.H., Chu K.W., Kwan S.W., Guan Y., Poon L.L., Peiris J.S. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China. Clin. Infect. Dis. 2005;40:1721–1729. - PMC - PubMed

[6] Chiu S.S., Chan K.H., Chu K.W., Kwan S.W., Guan Y., Poon L.L., Peiris J.S. Human coronavirus NL63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in Hong Kong, China. Clin. Infect. Dis. 2005;40:1721–1729. - PMC - PubMed

[7] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5:536–544. - PMC - PubMed

[8] Coronaviridae Study Group of the International Committee on Taxonomy of Viruses The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 2020;5:536–544. - PMC - PubMed

[9] Du L., He Y., Zhou Y., Liu S., Zheng B.J., Jiang S. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat. Rev. Microbiol. 2009;7:226–236. - PMC - PubMed

[10] Du L., He Y., Zhou Y., Liu S., Zheng B.J., Jiang S. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat. Rev. Microbiol. 2009;7:226–236. - PMC - PubMed

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Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

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Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

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