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Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated
by virus binding to the ACE2 cell-surface receptors
1–4
, followed by fusion of the virus and cell membranes to release the virus genome into
the cell. Both receptor binding and membrane fusion activities are mediated by the
virus spike glycoprotein
5–7
. As with other class-I membrane-fusion proteins, the spike protein is post-translationally
cleaved, in this case by furin, into the S1 and S2 components that remain associated
after cleavage
8–10
. Fusion activation after receptor binding is proposed to involve the exposure of
a second proteolytic site (S2′), cleavage of which is required for the release of
the fusion peptide
11,12
. Here we analyse the binding of ACE2 to the furin-cleaved form of the SARS-CoV-2
spike protein using cryo-electron microscopy. We classify ten different molecular
species, including the unbound, closed spike trimer, the fully open ACE2-bound trimer
and dissociated monomeric S1 bound to ACE2. The ten structures describe ACE2-binding
events that destabilize the spike trimer, progressively opening up, and out, the individual
S1 components. The opening process reduces S1 contacts and unshields the trimeric
S2 core, priming the protein for fusion activation and dissociation of ACE2-bound
S1 monomers. The structures also reveal refolding of an S1 subdomain after ACE2 binding
that disrupts interactions with S2, which involves Asp614
13–15
and leads to the destabilization of the structure of S2 proximal to the secondary
(S2′) cleavage site.
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.
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.
The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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