Structural basis of receptor recognition by SARS-CoV-2
Jian Shang, Gang Ye, Ke Shi, Yushun Wan, Chuming Luo, Hideki Aihara, Qibin Geng, Ashley Auerbach, Fang Li, Jian Shang, Gang Ye, Ke Shi, Yushun Wan, Chuming Luo, Hideki Aihara, Qibin Geng, Ashley Auerbach, Fang Li
Abstract
A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-191,2. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans3,4. Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
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References
- Li Q et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med, doi:10.1056/NEJMoa2001316 (2020).
- Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, doi:10.1016/s0140-6736(20)30183-5 (2020).
- Li F, Li WH, Farzan M & Harrison SC Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309, 1864–1868, doi:10.1126/science.1116480 (2005).
- Li WH et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426, 450–454, doi:10.1038/nature02145 (2003).
- Lee N et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. New England Journal of Medicine 348, 1986–1994 (2003).
- Peiris JSM et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 361, 1319–1325 (2003).
- Zhou P et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, doi:10.1038/s41586-020-2012-7 (2020).
- Perlman S & Netland J Coronaviruses post-SARS: update on replication and pathogenesis. Nature Reviews Microbiology 7, 439–450, doi:10.1038/nrmicro2147 (2009).
- Li F Structure, Function, and Evolution of Coronavirus Spike Proteins. Annual review of virology 3, 237–261, doi:10.1146/annurev-virology-110615-042301 (2016).
- Du LY et al. The spike protein of SARS-CoV - a target for vaccine and therapeutic development. Nature Reviews Microbiology 7, 226–236, doi:10.1038/nrmicro2090 (2009).
- Li F Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. Journal of Virology 82, 6984–6991, doi:10.1128/jvi.00442-08 (2008).
- Wu KL, Peng GQ, Wilken M, Geraghty RJ & Li F Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory Syndrome Coronavirus. Journal of Biological Chemistry 287, 8904–8911, doi:10.1074/jbc.M111.325803 (2012).
- Wan Y, Shang J, Graham R, Baric RS & Li F Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol, doi:10.1128/jvi.00127-20 (2020).
- Letko M, Marzi A & Munster V Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nature microbiology, doi:10.1038/s41564-020-0688-y (2020).
- Hoffmann M et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, doi:10.1016/j.cell.2020.02.052 (2020).
- Walls AC et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell, doi:10.1016/j.cell.2020.02.058 (2020).
- Lan J et al. Crystal structure of the 2019-nCoV spike receptor-binding domain bound with the ACE2 receptor. bioRxiv, 2020.2002.2019.956235, doi:10.1101/2020.02.19.956235 (2020).
- Pylaeva S, Brehm M & Sebastiani D Salt Bridge in Aqueous Solution: Strong Structural Motifs but Weak Enthalpic Effect. Scientific reports 8, 13626, doi:10.1038/s41598-018-31935-z (2018).
- Wrapp D et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, doi:10.1126/science.abb2507 (2020).
- Cui J, Li F & Shi ZL Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17, 181–192, doi:10.1038/s41579-018-0118-9 (2019).
- Yang Y et al. Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus. Proc Natl Acad Sci U S A 111, 12516–12521, doi:10.1073/pnas.1405889111 (2014).
- Xiao K et al. Isolation and Characterization of 2019-nCoV-like Coronavirus from Malayan Pangolins. bioRxiv, 2020.2002.2017.951335, doi:10.1101/2020.02.17.951335 (2020).
- Du L et al. MERS-CoV spike protein: a key target for antivirals. Expert opinion on therapeutic targets 21, 131–143, doi:10.1080/14728222.2017.1271415 (2017).
- Du L et al. Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines. Nature communications 7, 13473, doi:10.1038/ncomms13473 (2016).
- Otwinowski Z & Minor W in Macromolecular Crystallography, Pt A Vol. 276 Methods in Enzymology 307–326 (1997).
- Liebschner D et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta crystallographica. Section D, Structural biology 75, 861–877, doi:10.1107/s2059798319011471 (2019).
- Winn MD et al. Overview of the CCP4 suite and current developments. Acta crystallographica. Section D, Biological crystallography 67, 235–242, doi:10.1107/s0907444910045749 (2011).
- Emsley P & Cowtan K Coot: model-building tools for molecular graphics. Acta Crystallographica Section D-Biological Crystallography 60, 2126–2132, doi:10.1107/s0907444904019158 (2004).
- Sui JH et al. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proceedings of the National Academy of Sciences of the United States of America 101, 2536–2541 (2004).
- Li WH et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. Embo Journal 24, 1634–1643, doi:10.1038/sj.emboj.7600640 (2005).
- Sun C et al. SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development. bioRxiv, 2020.2002.2016.951723, doi:10.1101/2020.02.16.951723 (2020).
- Pesce AJ & Michael JG Artifacts and limitations of enzyme immunoassay. Journal of immunological methods 150, 111–119, doi:10.1016/0022-1759(92)90070-a (1992).
Source: PubMed