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

By R. Yan, Yuanyuan Zhang, Yaning Li, L. Xia, Yingying Guo, Qiang Zhou. 2020

4,530 citations recorded by the source corpus.

How SARS-CoV-2 binds to human cells Scientists are racing to learn the secrets of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan et al. present the structure of human ACE2 in complex with a membrane protein that it chaperones, B0AT1. In the context of this complex, ACE2 is a dimer. A further structure shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures provide a basis for the development of therapeutics targeting this crucial interaction. Science, this issue p. 1444 Insight into how SARS-CoV-2 binds its human receptor could provide a basis for the development of therapeutics. Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo–electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.

Subfields: Infectious Diseases, Molecular Biology

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Citations in the corpus

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “Structures of the SARS-CoV-2 S receptor-binding domain (RBD) in complex with ACE2 defined key residues involved in recognition and guide surveillance studies aiming to detect the emergence of mutants with altered binding affinity for ACE2 or distinct antigenicity (Lan et al., 2020; Shang et al., 202”
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants (2020, background): “Structure of the RBD (from PDB 6M17 (32)) with positions that are occupied by amino acids where mutations were acquired during replication in the presence of each monoclonal antibody or COV-NY plasma indicated.”
SARS-CoV-2: A Storm is Raging. (2020, neutral): “SARS-CoV-2 shares the same cellular receptor angiotensin-converting enzyme 2 (ACE2) as SARS-CoV (12), suggesting a similar tropism and route of entry.”
SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract (2020, neutral): “…(S) glycoprotein mediates viral entry via binding to the human angiotensin-converting enzyme (ACE2) (Hoffmann et al., 2020; Walls et al., 2020; Yan et al., 2020), followed by proteolytic processing by transmembrane protease, serine 2 (TMPRSS2), furin, and perhaps other lung proteases, which…”
Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2 (2020, neutral): “During the revision of our manuscript, the full-length hACE2 structure was reported to form a dimer in the presence of B0AT1 (an amino acid transporter), as revealed by cryoelectron microscopy (cryo-EM) analysis (Yan et al., 2020).”
Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant (2020, neutral): “The open conformation is required for ACE2 binding because the ACE2 binding site is partially shielded in the closed conformation (Shang et al., 2020; Yan et al., 2020), and the open conformation is believed tobeonpathway forSprotein-mediated fusionof the virionmembranewith the target cell membrane ”
Molecular Architecture of the SARS-CoV-2 Virus (2020, background): “angiotensin-converting enzyme-2 (ACE2) through the receptor binding domain (RBD), an essential step for membrane fusion (Hoffmann et al., 2020; Lan et al., 2020; Shang et al., 2020; Wang et al., 2020; Yan et al., 2020; Zhou et al., 2020).”