Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis

Kirchdoerfer, Robert N.; Wang, Nianshuang; Pallesen, Jesper; Wrapp, Daniel; Turner, Hannah L.; Cottrell, Christopher A.; Corbett, Kizzmekia S.; Graham, Barney S.; McLellan, Jason S.; Ward, Andrew B.

doi:10.1038/s41598-018-34171-7

Cited by 492 publications

(614 citation statements)

References 51 publications

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“…Recent structural work comparing recombinant S proteins from SARS-CoV and MERS-CoV in isolation and in complex with their cognate receptors or neutralizing antibodies suggested an activation mechanism for coronavirus fusion (Gui et al, 2017;Kirchdoerfer et al, 2018; Song et al, 2018;Walls et al, 2019;Yuan et al, 2017). Specifically, SARS-CoV and MERS-CoV S structures in complex with neutralizing antibodies isolated from survivors showed both antibodies competitively blocked receptor interaction, in agreement with previous surface plasmon resonance data (Corti et al, 2015;Rockx et al, 2008;Traggiai et al, 2004;Walls et al, 2019).…”

Section: Mechanism Of Fusion Activationsupporting

confidence: 78%

“…It is assembled from a large number of α-helices, an antiparallel core β-sheet, a β-rich connector domain and a stem helix leading to the heptad-repeat 2 (HR2) and the transmembrane region ( Fig. 1F) (Gui et al, 2017;Kirchdoerfer et al, 2016Kirchdoerfer et al, , 2018Pallesen et al, 2017;Shang et al, 2018a, b;Tortorici et al, 2019;Walls et al, 2016aWalls et al, , b, 2017bXiong et al, 2018;Yuan et al, 2017). Key S 2 features facilitating virus-cell fusion include the fusion peptide, two heptad repeat regions (named HR1 and HR2) and the transmembrane domain.…”

Section: Prefusion S Architecturementioning

confidence: 99%

“…Recent cryoEM studies revealed that MERS-CoV S and SARS-CoV S can adopt open and closed conformations in which the receptor binding site of domain B is exposed and occluded, respectively (Gui et al, 2017;Kirchdoerfer et al, 2018;Pallesen et al, 2017;Song et al, 2018;Walls et al, 2019;Yuan et al, 2017). In contrast, the MHV, HCoV-NL63, HCoV-HKU1, PDCoV, IBV and HCoV-OC43 S glycoproteins appear to only adopt a closed conformation (Kirchdoerfer et al, 2016;Shang et al, 2018a, b;Tortorici et al, 2019;Walls et al, 2016a, b;Xiong et al, 2018) and unknown trigger(s), besides proteolytic activation, might be necessary for these viruses to expose their receptor-binding motifs for recognition to occur.…”

Section: Diversity Of Cov Receptors and Entry Mechanismsmentioning

confidence: 99%

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Structural insights into coronavirus entry

Tortorici

Veesler

2019

Advances in Virus Research

776

720

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Coronaviruses (CoVs) have caused outbreaks of deadly pneumonia in humans since the beginning of the 21st century. The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and was responsible for an epidemic that spread to five continents with a fatality rate of 10% before being contained in 2003 (with additional cases reported in 2004). The Middle-East respiratory syndrome coronavirus (MERS-CoV) emerged in the Arabian Peninsula in 2012 and has caused recurrent outbreaks in humans with a fatality rate of 35%. SARS-CoV and MERS-CoV are zoonotic viruses that crossed the species barrier using bats/palm civets and dromedary camels, respectively. No specific treatments or vaccines have been approved against any of the six human coronaviruses, highlighting the need to investigate the principles governing viral entry and cross-species transmission as well as to prepare for zoonotic outbreaks which are likely to occur due to the large reservoir of CoVs found in mammals and birds. Here, we review our understanding of the infection mechanism used by coronaviruses derived from recent structural and biochemical studies.

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Section: Mechanism Of Fusion Activationsupporting

confidence: 78%

Section: Prefusion S Architecturementioning

confidence: 99%

Section: Diversity Of Cov Receptors and Entry Mechanismsmentioning

confidence: 99%

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Structural insights into coronavirus entry

Tortorici

Veesler

2019

Advances in Virus Research

776

720

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“…Since binding of ACE2 to the isolated B domain was Figure S3 and Tables S4 and S5. reported to have an equilibrium dissociation constant (K D ) in the nanomolar range (Li et al, 2005c), one would expect that full saturation should occur rapidly in the conditions of our experiments (100-fold concentration excess over the K D ). Previous reports, however, suggested a lower affinity of the fulllength S trimer, relative to the isolated B domain, for ACE2 (Kirchdoerfer et al, 2018;Matsuyama and Taguchi, 2009;Song et al, 2018). We propose that the conformational landscape of the B domains in the context of the SARS-CoV S trimer, sampling open and closed conformations, decreases the apparent binding affinity for ACE2 and S230 due to masking of their binding sites in the closed state.…”

Section: Activation Mechanism Of Coronavirus Membrane Fusionmentioning

confidence: 57%

Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

Walls

Xiong

Park

et al. 2019

Cell

637

792

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Graphical Abstract Highlights d MERS-CoV/SARS-CoV S composite glycan shields analyzed by cryo-EM and mass spectrometry d Structures of MERS-CoV/SARS-CoV S with neutralizing antibodies from survivors d LCA60 inhibits receptor binding by interacting with MERS-CoV S protein/glycans d S230 blocks receptor binding and triggers fusogenic rearrangements via functional mimicry In Brief Structural analysis of the SARS-CoV S and MERS-CoV S glycoproteins in complex with neutralizing antibodies from human survivors sheds light into the mechanisms of membrane fusion and neutralization Walls et al., SUMMARYRecent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Although the two antibodies studied blocked attachment to the host cell receptor, only the anti-SARS-CoV S antibody triggered fusogenic conformational changes via receptor functional mimicry. These results provide a structural framework for understanding coronavirus neutralization by human antibodies and shed light on activation of coronavirus membrane fusion, which takes place through a receptor-driven ratcheting mechanism.

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“…MERS-CoV S, however, uses domain A to recognize non-acetylated sialoside attachment receptors Park et al, 2019), which likely promote subsequent binding of domain B (S B ) to the entry receptor, dipeptidyl-peptidase 4 (Lu et al, 2013;Raj et al, 2013). SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) via S B to enter target cells (Ge et al, 2013;Kirchdoerfer et al, 2018;Li et al, 2005a;Li et al, 2003;Song et al, 2018;Yang et al, 2015a).…”

Section: Introductionmentioning

confidence: 99%

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Walls

Park

Tortorici

et al. 2020

Cell

8,011

258

8,384

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Graphical AbstractHighlights d SARS-CoV-2 uses ACE2 to enter target cells d SARS-CoV-2 and SARS-CoV bind with similar affinities to ACE2 d Structures of SARS-CoV-2 spike glycoprotein in two conformations d SARS-CoV polyclonal antibodies inhibit SARS-CoV-2 spikemediated entry into cellsIn Brief SARS-CoV-2, a newly emerged pathogen spreading worldwide, binds with high affinity to human ACE2 and uses it as an entry receptor to invade target cells.Cryo-EM structures of the SARS-CoV-2 spike glycoprotein in two distinct conformations, along with inhibition of spike-mediated entry by SARS-CoV polyclonal antibodies, provide a blueprint for the design of vaccines and therapeutics. SUMMARYThe emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S 1 /S 2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

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Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis

Cited by 492 publications

References 51 publications

Structural insights into coronavirus entry

Structural insights into coronavirus entry

Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

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