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

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          Summary

          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.

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          Highlights

          • •

            SARS-CoV-2 interacts with hACE2 via S protein CTD

          • •

            A 2.5-Å structure of SARS-CoV-2-CTD in complex with hACE2 is resolved

          • •

            The SARS-CoV-2-CTD displays stronger affinity for hACE2 compared with SARS-RBD

          • •

            SARS-CoV-2 -CTD is antigenically different from SARS-RBD

          Abstract

          The crystal structure of the C-terminal domain of the SARS-CoV-2 spike protein in complex with human ACE2 reveals insights into the mechanisms of binding of this virus and its differences from SARS.

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Na Zhu, Dingyu Zhang, Wenling Wang … (2020)
          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)
            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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              SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

              Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
              Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
              Article 0 comments Cited 9635 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jinghua Yan
                Jianxun Qi
                Journal
                Journal ID (nlm-ta): Cell
                Journal ID (iso-abbrev): Cell
                Title: Cell
                Publisher: Elsevier Inc.
                ISSN (Print): 0092-8674
                ISSN (Electronic): 1097-4172
                Publication date PMC-release: 9 April 2020
                Publication date (Electronic): 9 April 2020
                Affiliations
                [1 ]CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
                [2 ]Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen 518112, China
                [3 ]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
                [4 ]University of the Chinese Academy of Sciences, Beijing 100049, China
                [5 ]Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Biotechnology, Tianjin 300308, China
                [6 ]College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu 030801, China
                [7 ]Institute of Physical Science and Information, Anhui University, Hefei 230039, China
                [8 ]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
                [9 ]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
                [11 ]Department of Microbiology, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region 999077, China
                [12 ]Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China
                [13 ]College of Life Science, University of the Chinese Academy of Sciences, Beijing 100049, China
                [14 ]Savaid Medical School, University of the Chinese Academy of Sciences, Beijing 100049, China
                Author notes
                [∗ ]Corresponding author yanjh@ 123456im.ac.cn
                [∗∗ ]Corresponding author jxqi@ 123456im.ac.cn
                [15]

                These authors contributed equally

                [16]

                Lead Contact

                Article
                Publisher ID: S0092-8674(20)30338-X
                DOI: 10.1016/j.cell.2020.03.045
                PMC ID: 7144619
                PubMed ID: 32275855
                SO-VID: f395bf48-5afd-45a1-aaaf-16d3ac5a3f89
                Copyright © © 2020 Elsevier Inc.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 28 February 2020
                Date revision received : 14 March 2020
                Date accepted : 19 March 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Keywords: sars-cov-2,ctd,receptor binding domain,receptor,ace2,crystal structure,immunogenicity
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: sars-cov-2, ctd, receptor binding domain, receptor, ace2, crystal structure, immunogenicity

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