Research Article

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

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Science  27 Mar 2020:
Vol. 367, Issue 6485, pp. 1444-1448
DOI: 10.1126/science.abb2762

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  • RE: ACE2 Homodimerization Affects Binding of SARS-CoV-2 Spike Protein
    • Swarkar Sharma, Coordinator, Human Genetics Research Group, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India
    • Other Contributors:
      • Inderpal Singh, Independent Researcher, Bioinfores Pvt. Ltd., R. S. Pura, Jammu, Jammu and Kashmir, India;
      • Shazia Haider, Assistant Professor, Jaypee Institute of Information Technology, Noida, sector-62, Uttar Pradesh, India
      • Md. Zubbair Malik, Young Scientist, School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India
      • Kalaiarasan Ponnusamy, Young Scientist, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
      • Ekta Rai, Assistant Professor, Human Genetics Research Group, School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir, India

    Yan et.al. 2020 proposed the binding of two SARS-CoV-2 Spike Glycoproteins (SGs) with Angiotensin-converting enzyme 2 (ACE2) homodimer without affecting each other or any structural hindrance (1). We appreciate the extensive work done and important findings. However, we believe binding of two SGs to ACE2 homodimer is only possible in modelled version as given, but not naturally. At the same time, the alternate explanation we provide may help find an answer to the question that despite being a receptor for SARS-CoV-2, how can ACE2 still perform its physiological role of protection from severe Lung injury, in some COVID-19 patients (2). Alignment of receptor binding domain (RBD) (6M17.pdb), with the prefusion SARS-CoV-2 SG (6VSB.pdb), in the optimal ACE2 binding conformation (Figure 1’) provided in detailed manuscript preprint at https://www.biorxiv.org/content/10.1101/2020.04.24.050534v3 with “up CTD1” and “open S1 subunit” (1, 3)has shown no steric clash with the ACE2 or another SG, as reported (1). We extended the evaluation and noted that both SGs protrude radially outward from ACE2 protease domains (PDs). RBDs are 6 nanometer (nm) apart at PDs and anchorage sites of SGs on virus membrane are approximately at a distance of 27 nm (Figure 1’b). However, considering the reported inter spike distance of 13-15 nm (4) on the viral shell, given almost similar sizes of SARS-CoV (4, 5) and SARS-CoV-2 (6), S...

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    Competing Interests: The authors declare no competing interests associated with MS. For declaration purposes, SS is founder, chief scientific advisor of a startup "Biodroid Innovations Pvt Ltd" and IP is director of "Bioinfores Pvt. Ltd."”
  • RE: Molecular mechanism of SARS-CoV-2-RBD and human ACE2 from their 3D structures
    • Minh N. Nguyen, Senior Research Scientists, 1. Bioinformatics Institute, Singapore 138671; 2. Innovations in Food & Chemical Safety Programme (IFCS), A*STAR
    • Other Contributors:
      • Chandra S. Verma, Senior Principal Investigator, Bioinformatics Institute, 30 Biopolis Street, #07-01, Matrix, Singapore 138671

    Computational studies of human-virus protein-protein interactions from their 3D structures have been playing important roles to discover successful drugs for various viruses such as HIV-1, hepatitis C virus, and norovirus (1). The spike receptor-binding domain of SARS-CoV-2 (SARS-CoV-2-RBD) binds to human angiotensin-converting enzyme 2 (ACE2) to initiate entry into human cells (2), which is currently a crucial target for anti-viral therapeutics.

    Since Science has recently published two papers for cryo-EM structures of SARS-CoV-2 spike protein (PDB code: 6VSB, resolution: 3.46Å) (3), SARS-CoV-2-RBD and human ACE2 (PDB code: 6M17, resolution: 2.90Å) (4), and Protein Data Bank released a new crystal structures of SARS-CoV-2-RBD and human ACE2 on 18 March 2020 (PDB code: 6LZG, resolution: 2.50Å) (5), and Nature just published a new paper for another crystal structures of SARS-CoV-2-RBD and human ACE2 on 30 March 2020 (PDB code: 6M0J, resolution: 2.45Å) (6), we can start to ask questions about (i) how these structures could help us understand the underlying principles and molecular mechanisms of interactions between SARS-CoV-2-RBD and ACE2, and (ii) which structure we should select for further study to facilitate the development of therapeutics.

    In order to answer these questions, we have used our programs (7) for dissecting the contributions of hydrogen bonds (Hbond), hydrophobic interactions, van der Waals interactions (vdW), ionic interactions, and int...

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    Competing Interests: None declared.
  • RE: ACE-inhibitors and Angiotensin II receptor blockers: are they dangerous in case of SARS-CoV-2-infection?
    • Adriana Albini, Director of Vascular Biology, Scientific and Technology Pole, IRCCS Multimedica, Milan, Italy
    • Other Contributors:
      • Giovanni Di Guardo, Professor, University of Teramo, Faculty of Veterinary Medicine, 64100 Teramo, Italy
      • Michele Lombardo, Director of Cardiology, Cardiology Unit, San Giuseppe Hospital-MultiMedica, Milan, Italy

    Your Science paper (1) reported the structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. This confirms that the novel virus SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as a receptor similar to SARS-CoV. Zhou et al demonstrated that ACE2 overexpressing in vitro can allow SARS-CoV-2 infection and replication, mediating CoV spike protein's interaction with the ACE2 (2). These findings provide important insights into the molecular basis of the angiotensin/renin system for coronavirus recognition and infection.
    In clinical practice, Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers (ARB) are extensively used for the treatment of various cardiovascular diseases, like hypertension, ischemic or idiopathic heart disease, and diabetic nephropathy.
    It has been underlined that in a rat model, the cardiac ACE2 mRNA expression, after treatment with the ACE-inhibitor lisinopril, increased in comparison to the controls, and also after treatment with the angiotensin II (AT)1 receptor blocker losartan (3).
    Among the clinicians, the fear has been therefore raising that the ACE-2 overexpression after treatment with the two classes of drugs (4) could favor the viral lung tissue colonization in SARS-CoV-2-infected patients.
    In the opposite direction, it has recently been suggested that the ARB could potentially be useful in clinical course of COVID-19 patients (5).
    The above cited, at t...

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    Competing Interests: None declared.

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