Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Identifieur interne : 001469 ( Pmc/Corpus ); précédent : 001468; suivant : 001470Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Auteurs : Daniel Wrapp ; Nianshuang Wang ; Kizzmekia S. Corbett ; Jory A. Goldsmith ; Ching-Lin Hsieh ; Olubukola Abiona ; Barney S. Graham ; Jason S. MclellanSource :
- Science (New York, N.y.) [ 0036-8075 ] ; 2020.
Abstract
The World Health Organization has declared the outbreak of a novel coronavirus
(2019-nCoV) to be a public health emergency of international concern. The virus binds to
host cells through its trimeric spike glycoprotein, making this protein a key target for
potential therapies and diagnostics. Wrapp
Url:
DOI: 10.1126/science.abb2507
PubMed: 32075877
PubMed Central: 7164637
Links to Exploration step
PMC:7164637Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cryo-EM structure of the 2019-nCoV spike in the prefusion
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<author><name sortKey="Wrapp, Daniel" sort="Wrapp, Daniel" uniqKey="Wrapp D" first="Daniel" last="Wrapp">Daniel Wrapp</name>
<affiliation><nlm:aff id="aff1">Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</nlm:aff>
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<author><name sortKey="Wang, Nianshuang" sort="Wang, Nianshuang" uniqKey="Wang N" first="Nianshuang" last="Wang">Nianshuang Wang</name>
<affiliation><nlm:aff id="aff1">Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</nlm:aff>
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<author><name sortKey="Corbett, Kizzmekia S" sort="Corbett, Kizzmekia S" uniqKey="Corbett K" first="Kizzmekia S." last="Corbett">Kizzmekia S. Corbett</name>
<affiliation><nlm:aff id="aff2">Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff>
</affiliation>
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<author><name sortKey="Goldsmith, Jory A" sort="Goldsmith, Jory A" uniqKey="Goldsmith J" first="Jory A." last="Goldsmith">Jory A. Goldsmith</name>
<affiliation><nlm:aff id="aff1">Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</nlm:aff>
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<author><name sortKey="Hsieh, Ching Lin" sort="Hsieh, Ching Lin" uniqKey="Hsieh C" first="Ching-Lin" last="Hsieh">Ching-Lin Hsieh</name>
<affiliation><nlm:aff id="aff1">Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</nlm:aff>
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<author><name sortKey="Abiona, Olubukola" sort="Abiona, Olubukola" uniqKey="Abiona O" first="Olubukola" last="Abiona">Olubukola Abiona</name>
<affiliation><nlm:aff id="aff2">Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff>
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<author><name sortKey="Graham, Barney S" sort="Graham, Barney S" uniqKey="Graham B" first="Barney S." last="Graham">Barney S. Graham</name>
<affiliation><nlm:aff id="aff2">Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</nlm:aff>
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<author><name sortKey="Mclellan, Jason S" sort="Mclellan, Jason S" uniqKey="Mclellan J" first="Jason S." last="Mclellan">Jason S. Mclellan</name>
<affiliation><nlm:aff id="aff1">Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</nlm:aff>
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<series><title level="j">Science (New York, N.y.)</title>
<idno type="ISSN">0036-8075</idno>
<idno type="eISSN">1095-9203</idno>
<imprint><date when="2020">2020</date>
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<front><div type="abstract" xml:lang="en"><title>Structure of the nCoV trimeric spike</title>
<p>The World Health Organization has declared the outbreak of a novel coronavirus
(2019-nCoV) to be a public health emergency of international concern. The virus binds to
host cells through its trimeric spike glycoprotein, making this protein a key target for
potential therapies and diagnostics. Wrapp <italic>et al.</italic>
determined a
3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by
cryo–electron microscopy. Using biophysical assays, the authors show that this
protein binds at least 10 times more tightly than the corresponding spike protein of
severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor.
They also tested three antibodies known to bind to the SARS-CoV spike protein but did not
detect binding to the 2019-nCoV spike protein. These studies provide valuable information
to guide the development of medical counter-measures for 2019-nCoV.</p>
<p><italic>Science</italic>
, this issue p. <ext-link ext-link-type="doi" xlink:href="10.1126/science.abb2507">1260</ext-link>
</p>
</div>
</front>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Science</journal-id>
<journal-id journal-id-type="iso-abbrev">Science</journal-id>
<journal-id journal-id-type="publisher-id">SCIENCE</journal-id>
<journal-id journal-id-type="hwp">science</journal-id>
<journal-title-group><journal-title>Science (New York, N.y.)</journal-title>
</journal-title-group>
<issn pub-type="ppub">0036-8075</issn>
<issn pub-type="epub">1095-9203</issn>
<publisher><publisher-name>American Association for the Advancement of Science</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">32075877</article-id>
<article-id pub-id-type="pmc">7164637</article-id>
<article-id pub-id-type="publisher-id">abb2507</article-id>
<article-id pub-id-type="doi">10.1126/science.abb2507</article-id>
<article-categories><subj-group subj-group-type="article-type"><subject>Report</subject>
</subj-group>
<subj-group subj-group-type="heading"><subject>Reports</subject>
</subj-group>
<subj-group subj-group-type="legacy-article-type"><subject>Reports</subject>
</subj-group>
<subj-group subj-group-type="field"><subject>Biochem</subject>
<subject>Microbio</subject>
</subj-group>
</article-categories>
<title-group><article-title>Cryo-EM structure of the 2019-nCoV spike in the prefusion
conformation</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-0538-9647</contrib-id>
<name><surname>Wrapp</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="afn1">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7569-011X</contrib-id>
<name><surname>Wang</surname>
<given-names>Nianshuang</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="afn1">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2641-4688</contrib-id>
<name><surname>Corbett</surname>
<given-names>Kizzmekia S.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Goldsmith</surname>
<given-names>Jory A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hsieh</surname>
<given-names>Ching-Lin</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2745-1691</contrib-id>
<name><surname>Abiona</surname>
<given-names>Olubukola</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-8112-0853</contrib-id>
<name><surname>Graham</surname>
<given-names>Barney S.</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3991-542X</contrib-id>
<name><surname>McLellan</surname>
<given-names>Jason S.</given-names>
</name>
<xref ref-type="award" rid="award585141"></xref>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1">†</xref>
</contrib>
<aff id="aff1"><label>1</label>
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA.</aff>
<aff id="aff2"><label>2</label>
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.</aff>
</contrib-group>
<author-notes><fn id="afn1" fn-type="equal"><label>*</label>
<p>These authors contributed equally to this work.</p>
</fn>
<corresp id="cor1"><label>†</label>
Corresponding author. Email: <email xlink:href="jmclellan@austin.utexas.edu">jmclellan@austin.utexas.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>13</day>
<month>3</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>19</day>
<month>2</month>
<year>2020</year>
</pub-date>
<volume>367</volume>
<issue>6483</issue>
<fpage>1260</fpage>
<lpage>1263</lpage>
<history><date date-type="received"><day>10</day>
<month>2</month>
<year>2020</year>
</date>
<date date-type="accepted"><day>17</day>
<month>2</month>
<year>2020</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2020 The Authors, some rights reserved; exclusive
licensee American Association for the Advancement of Science. No claim to original U.S.
Government Works</copyright-statement>
<copyright-year>2020</copyright-year>
<copyright-holder>American Association for the Advancement of Science</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><ali:license_ref specific-use="vor" start_date="2020-03-04">https://creativecommons.org/licenses/by/4.0/</ali:license_ref>
<license-p>This open access article is distributed under <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License 4.0 (CC BY)</ext-link>
.</license-p>
</license>
</permissions>
<abstract abstract-type="editor"><title>Structure of the nCoV trimeric spike</title>
<p>The World Health Organization has declared the outbreak of a novel coronavirus
(2019-nCoV) to be a public health emergency of international concern. The virus binds to
host cells through its trimeric spike glycoprotein, making this protein a key target for
potential therapies and diagnostics. Wrapp <italic>et al.</italic>
determined a
3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by
cryo–electron microscopy. Using biophysical assays, the authors show that this
protein binds at least 10 times more tightly than the corresponding spike protein of
severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor.
They also tested three antibodies known to bind to the SARS-CoV spike protein but did not
detect binding to the 2019-nCoV spike protein. These studies provide valuable information
to guide the development of medical counter-measures for 2019-nCoV.</p>
<p><italic>Science</italic>
, this issue p. <ext-link ext-link-type="doi" xlink:href="10.1126/science.abb2507">1260</ext-link>
</p>
</abstract>
<abstract abstract-type="teaser"><p>The overall structure of the 2019-nCoV spike (S) protein resembles that of SARS-CoV S,
but 2019-nCoV S binds more tightly to the host receptor.</p>
</abstract>
<abstract><p>The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has
been declared a public health emergency of international concern. The CoV spike (S)
glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To
facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution
cryo–electron microscopy structure of the 2019-nCoV S trimer in the prefusion
conformation. The predominant state of the trimer has one of the three receptor-binding
domains (RBDs) rotated up in a receptor-accessible conformation. We also provide
biophysical and structural evidence that the 2019-nCoV S protein binds
angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute
respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV
RBD-specific monoclonal antibodies and found that they do not have appreciable binding to
2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two
RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of
medical countermeasures to address the ongoing public health crisis.</p>
</abstract>
<funding-group><award-group id="award585141"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/100000060</institution-id>
<institution>National Institute of Allergy and Infectious Diseases</institution>
</institution-wrap>
</funding-source>
<award-id>R01-AI127521</award-id>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>Editor</meta-name>
<meta-value>Valda Vinson</meta-value>
</custom-meta>
<custom-meta><meta-name>Copyeditor</meta-name>
<meta-value>Suzanne White</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><p>The novel coronavirus 2019-nCoV has recently emerged as a human pathogen in the city of Wuhan
in China’s Hubei province, causing fever, severe respiratory illness, and
pneumonia—a disease recently named COVID-19 (<xref rid="R1" ref-type="bibr"><italic>1</italic>
</xref>
, <xref rid="R2" ref-type="bibr"><italic>2</italic>
</xref>
).
According to the World Health Organization (WHO), as of 16 February 2020, there had been
>51,000 confirmed cases globally, leading to at least 1600 deaths. The emerging pathogen
was rapidly characterized as a new member of the betacoronavirus genus, closely related to
several bat coronaviruses and to severe acute respiratory syndrome coronavirus (SARS-CoV)
(<xref rid="R3" ref-type="bibr"><italic>3</italic>
</xref>
, <xref rid="R4" ref-type="bibr"><italic>4</italic>
</xref>
). Compared with SARS-CoV, 2019-nCoV appears to be more readily
transmitted from human to human, spreading to multiple continents and leading to the
WHO’s declaration of a Public Health Emergency of International Concern (PHEIC) on 30
January 2020 (<xref rid="R1" ref-type="bibr"><italic>1</italic>
</xref>
, <xref rid="R5" ref-type="bibr"><italic>5</italic>
</xref>
, <xref rid="R6" ref-type="bibr"><italic>6</italic>
</xref>
).</p>
<p>2019-nCoV makes use of a densely glycosylated spike (S) protein to gain entry into host
cells. The S protein is a trimeric class I fusion protein that exists in a metastable
prefusion conformation that undergoes a substantial structural rearrangement to fuse the viral
membrane with the host cell membrane (<xref rid="R7" ref-type="bibr"><italic>7</italic>
</xref>
, <xref rid="R8" ref-type="bibr"><italic>8</italic>
</xref>
). This
process is triggered when the S1 subunit binds to a host cell receptor. Receptor binding
destabilizes the prefusion trimer, resulting in shedding of the S1 subunit and transition of
the S2 subunit to a stable postfusion conformation (<xref rid="R9" ref-type="bibr"><italic>9</italic>
</xref>
). To engage a host cell receptor, the receptor-binding domain
(RBD) of S1 undergoes hinge-like conformational movements that transiently hide or expose the
determinants of receptor binding. These two states are referred to as the “down”
conformation and the “up” conformation, where down corresponds to the
receptor-inaccessible state and up corresponds to the receptor-accessible state, which is
thought to be less stable (<xref rid="R10" ref-type="bibr"><italic>10</italic>
</xref>
–<xref rid="R13" ref-type="bibr"><italic>13</italic>
</xref>
). Because of the indispensable function of the S protein, it
represents a target for antibody-mediated neutralization, and characterization of the
prefusion S structure would provide atomic-level information to guide vaccine design and
development.</p>
<p>Based on the first reported genome sequence of 2019-nCoV (<xref rid="R4" ref-type="bibr"><italic>4</italic>
</xref>
), we expressed ectodomain residues 1 to 1208 of 2019-nCoV S,
adding two stabilizing proline mutations in the C-terminal S2 fusion machinery using a
previous stabilization strategy that proved effective for other betacoronavirus S proteins
(<xref rid="R11" ref-type="bibr"><italic>11</italic>
</xref>
, <xref rid="R14" ref-type="bibr"><italic>14</italic>
</xref>
). <xref ref-type="fig" rid="F1">Figure 1A</xref>
shows the
domain organization of the expression construct, and figure S1 shows the purification process.
We obtained ~0.5 mg/liter of the recombinant prefusion-stabilized S ectodomain from FreeStyle
293 cells and purified the protein to homogeneity by affinity chromatography and
size-exclusion chromatography (fig. S1). Cryo–electron microscopy (cryo-EM) grids were
prepared using this purified, fully glycosylated S protein, and preliminary screening revealed
a high particle density with little aggregation near the edges of the holes.</p>
<fig id="F1" fig-type="figure" orientation="portrait" position="float"><label>Fig. 1</label>
<caption><title>Structure of 2019-nCoV S in the prefusion conformation.</title>
<p>(<bold>A</bold>
) Schematic of 2019-nCoV S primary structure colored by domain. Domains
that were excluded from the ectodomain expression construct or could not be visualized in
the final map are colored white. SS, signal sequence; S2′, S2′ protease
cleavage site; FP, fusion peptide; HR1, heptad repeat 1; CH, central helix; CD, connector
domain; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail. Arrows
denote protease cleavage sites. (<bold>B</bold>
) Side and top views of the prefusion
structure of the 2019-nCoV S protein with a single RBD in the up conformation. The two RBD
down protomers are shown as cryo-EM density in either white or gray and the RBD up
protomer is shown in ribbons colored corresponding to the schematic in (A).</p>
</caption>
<graphic xlink:href="367_1260_F1"></graphic>
</fig>
<p>After collecting and processing 3207 micrograph movies, we obtained a 3.5-Å-resolution
three-dimensional (3D) reconstruction of an asymmetrical trimer in which a single RBD was
observed in the up conformation. (<xref ref-type="fig" rid="F1">Fig. 1B</xref>
, fig. S2, and
table S1). Because of the small size of the RBD (~21 kDa), the asymmetry of this conformation
was not readily apparent until ab initio 3D reconstruction and classification were performed
(<xref ref-type="fig" rid="F1">Fig. 1B</xref>
and fig. S3). By using the 3D variability
feature in cryoSPARC v2 (<xref rid="R15" ref-type="bibr"><italic>15</italic>
</xref>
), we
observed breathing of the S1 subunits as the RBD underwent a hinge-like movement, which likely
contributed to the relatively poor local resolution of S1 compared with the more stable S2
subunit (movies S1 and S2). This seemingly stochastic RBD movement has been captured during
structural characterization of the closely related betacoronaviruses SARS-CoV and MERS-CoV, as
well as the more distantly related alphacoronavirus porcine epidemic diarrhea virus (PEDV)
(<xref rid="R10" ref-type="bibr"><italic>10</italic>
</xref>
, <xref rid="R11" ref-type="bibr"><italic>11</italic>
</xref>
, <xref rid="R13" ref-type="bibr"><italic>13</italic>
</xref>
,
<xref rid="R16" ref-type="bibr"><italic>16</italic>
</xref>
). The observation of this
phenomenon in 2019-nCoV S suggests that it shares the same mechanism of triggering that is
thought to be conserved among the Coronaviridae, wherein receptor binding to exposed RBDs
leads to an unstable three-RBD up conformation that results in shedding of S1 and refolding of
S2 (<xref rid="R11" ref-type="bibr"><italic>11</italic>
</xref>
, <xref rid="R12" ref-type="bibr"><italic>12</italic>
</xref>
).</p>
<p>Because the S2 subunit appeared to be a symmetric trimer, we performed a 3D refinement
imposing C3 symmetry, resulting in a 3.2-Å-resolution map with excellent density for
the S2 subunit. Using both maps, we built most of the 2019-nCoV S ectodomain, including
glycans at 44 of the 66 <italic>N</italic>
-linked glycosylation sites per trimer (fig. S4).
Our final model spans S residues 27 to 1146, with several flexible loops omitted. Like all
previously reported coronavirus S ectodomain structures, the density for 2019-nCoV S begins to
fade after the connector domain, reflecting the flexibility of the heptad repeat 2 domain in
the prefusion conformation (fig. S4A) (<xref rid="R13" ref-type="bibr"><italic>13</italic>
</xref>
, <xref rid="R16" ref-type="bibr"><italic>16</italic>
</xref>
–<xref rid="R18" ref-type="bibr"><italic>18</italic>
</xref>
).</p>
<p>The overall structure of 2019-nCoV S resembles that of SARS-CoV S, with a root mean square
deviation (RMSD) of 3.8 Å over 959 Cα atoms (<xref ref-type="fig" rid="F2">Fig.
2A</xref>
). One of the larger differences between these two structures (although still
relatively minor) is the position of the RBDs in their respective down conformations. Whereas
the SARS-CoV RBD in the down conformation packs tightly against the N-terminal domain (NTD) of
the neighboring protomer, the 2019-nCoV RBD in the down conformation is angled closer to the
central cavity of the trimer (<xref ref-type="fig" rid="F2">Fig. 2B</xref>
). Despite this
observed conformational difference, when the individual structural domains of 2019-nCoV S are
aligned to their counterparts from SARS-CoV S, they reflect the high degree of structural
homology between the two proteins, with the NTDs, RBDs, subdomains 1 and 2 (SD1 and SD2), and
S2 subunits yielding individual RMSD values of 2.6 Å, 3.0 Å, 2.7 Å, and
2.0 Å, respectively (<xref ref-type="fig" rid="F2">Fig. 2C</xref>
).</p>
<fig id="F2" fig-type="figure" orientation="portrait" position="float"><label>Fig. 2</label>
<caption><title>Structural comparison between 2019-nCoV S and SARS-CoV S.</title>
<p>(<bold>A</bold>
) Single protomer of 2019-nCoV S with the RBD in the down conformation
(left) is shown in ribbons colored according to <xref ref-type="fig" rid="F1">Fig.
1</xref>
. A protomer of 2019-nCoV S in the RBD up conformation is shown (center) next to
a protomer of SARS-CoV S in the RBD up conformation (right), displayed as ribbons and
colored white (PDB ID: 6CRZ). (<bold>B</bold>
) RBDs of 2019-nCoV and SARS-CoV aligned
based on the position of the adjacent NTD from the neighboring protomer. The 2019-nCoV RBD
is colored green and the SARS-CoV RBD is colored white. The 2019-nCoV NTD is colored blue.
(<bold>C</bold>
) Structural domains from 2019-nCoV S have been aligned to their
counterparts from SARS-CoV S as follows: NTD (top left), RBD (top right), SD1 and SD2
(bottom left), and S2 (bottom right).</p>
</caption>
<graphic xlink:href="367_1260_F2"></graphic>
</fig>
<p>2019-nCoV S shares 98% sequence identity with the S protein from the bat coronavirus RaTG13,
with the most notable variation arising from an insertion in the S1/S2 protease cleavage site
that results in an “RRAR” furin recognition site in 2019-nCoV (<xref rid="R19" ref-type="bibr"><italic>19</italic>
</xref>
) rather than the single arginine in
SARS-CoV (fig. S5) (<xref rid="R20" ref-type="bibr"><italic>20</italic>
</xref>
–<xref rid="R23" ref-type="bibr"><italic>23</italic>
</xref>
). Notably, amino acid insertions that
create a polybasic furin site in a related position in hemagglutinin proteins are often found
in highly virulent avian and human influenza viruses (<xref rid="R24" ref-type="bibr"><italic>24</italic>
</xref>
). In the structure reported here, the S1/S2 junction is in a
disordered, solvent-exposed loop. In addition to this insertion of residues in the S1/S2
junction, 29 variant residues exist between 2019-nCoV S and RaTG13 S, with 17 of these
positions mapping to the RBD (figs. S5 and S6). We also analyzed the 61 available 2019-nCoV S
sequences in the Global Initiative on Sharing All Influenza Data database (<ext-link ext-link-type="uri" xlink:href="https://www.gisaid.org/">https://www.gisaid.org/</ext-link>
)
and found that there were only nine amino acid substitutions among all deposited sequences.
Most of these substitutions are relatively conservative and are not expected to have a
substantial effect on the structure or function of the 2019-nCoV S protein (fig. S6).</p>
<p>Recent reports demonstrating that 2019-nCoV S and SARS-CoV S share the same functional host
cell receptor, angiotensin-converting enzyme 2 (ACE2) (<xref rid="R22" ref-type="bibr"><italic>22</italic>
</xref>
, <xref rid="R25" ref-type="bibr"><italic>25</italic>
</xref>
–<xref rid="R27" ref-type="bibr"><italic>27</italic>
</xref>
), prompted us to quantify the kinetics of this interaction by
surface plasmon resonance. ACE2 bound to the 2019-nCoV S ectodomain with ~15 nM affinity,
which is ~10- to 20-fold higher than ACE2 binding to SARS-CoV S (<xref ref-type="fig" rid="F3">Fig. 3A</xref>
and fig. S7) (<xref rid="R14" ref-type="bibr"><italic>14</italic>
</xref>
).
We also formed a complex of ACE2 bound to the 2019-nCoV S ectodomain and observed it by
negative-stain EM, which showed that it strongly resembled the complex formed between SARS-CoV
S and ACE2 that has been observed at high resolution by cryo-EM (<xref ref-type="fig" rid="F3">Fig. 3B</xref>
) (<xref rid="R14" ref-type="bibr"><italic>14</italic>
</xref>
, <xref rid="R28" ref-type="bibr"><italic>28</italic>
</xref>
). The high affinity of 2019-nCoV S for
human ACE2 may contribute to the apparent ease with which 2019-nCoV can spread from human to
human (<xref rid="R1" ref-type="bibr"><italic>1</italic>
</xref>
); however, additional studies
are needed to investigate this possibility.</p>
<fig id="F3" fig-type="figure" orientation="portrait" position="float"><label>Fig. 3</label>
<caption><title>2019-nCoV S binds human ACE2 with high affinity.</title>
<p>(<bold>A</bold>
) Surface plasmon resonance sensorgram showing the binding kinetics for
human ACE2 and immobilized 2019-nCoV S. Data are shown as black lines, and the best fit of
the data to a 1:1 binding model is shown in red. (<bold>B</bold>
) Negative-stain EM 2D
class averages of 2019-nCoV S bound by ACE2. Averages have been rotated so that ACE2 is
positioned above the 2019-nCoV S protein with respect to the viral membrane. A diagram
depicting the ACE2-bound 2019-nCoV S protein is shown (right) with ACE2 in blue and S
protein protomers colored tan, pink, and green.</p>
</caption>
<graphic xlink:href="367_1260_F3"></graphic>
</fig>
<p>The overall structural homology and shared receptor usage between SARS-CoV S and 2019-nCoV S
prompted us to test published SARS-CoV RBD-directed monoclonal antibodies (mAbs) for
cross-reactivity to the 2019-nCoV RBD (<xref ref-type="fig" rid="F4">Fig. 4A</xref>
). A
2019-nCoV RBD-SD1 fragment (S residues 319 to 591) was recombinantly expressed, and
appropriate folding of this construct was validated by measuring ACE2 binding using biolayer
interferometry (BLI) (<xref ref-type="fig" rid="F4">Fig. 4B</xref>
). Cross-reactivity of the
SARS-CoV RBD-directed mAbs S230, m396, and 80R was then evaluated by BLI (<xref rid="R12" ref-type="bibr"><italic>12</italic>
</xref>
, <xref rid="R29" ref-type="bibr"><italic>29</italic>
</xref>
–<xref rid="R31" ref-type="bibr"><italic>31</italic>
</xref>
). Despite the relatively high degree of structural homology
between the 2019-nCoV RBD and the SARS-CoV RBD, no binding to the 2019-nCoV RBD could be
detected for any of the three mAbs at the concentration tested (1 μM) (<xref ref-type="fig" rid="F4">Fig. 4C</xref>
), in contrast to the strong binding that we observed
to the SARS-CoV RBD (fig. S8). Although the epitopes of these three antibodies represent a
relatively small percentage of the surface area of the 2019-nCoV RBD, the lack of observed
binding suggests that SARS-directed mAbs will not necessarily be cross-reactive and that
future antibody isolation and therapeutic design efforts will benefit from using 2019-nCoV S
proteins as probes.</p>
<fig id="F4" fig-type="figure" orientation="portrait" position="float"><label>Fig. 4</label>
<caption><title>Antigenicity of the 2019-nCoV RBD.</title>
<p>(<bold>A</bold>
) SARS-CoV RBD shown as a white molecular surface (PDB ID: 2AJF), with
residues that vary in the 2019-nCoV RBD colored red. The ACE2-binding site is outlined
with a black dashed line. (<bold>B</bold>
) Biolayer interferometry sensorgram showing
binding to ACE2 by the 2019-nCoV RBD-SD1. Binding data are shown as a black line, and the
best fit of the data to a 1:1 binding model is shown in red. (<bold>C</bold>
) Biolayer
interferometry to measure cross-reactivity of the SARS-CoV RBD-directed antibodies S230,
m396, and 80R. Sensor tips with immobilized antibodies were dipped into wells containing
2019-nCoV RBD-SD1, and the resulting data are shown as a black line.</p>
</caption>
<graphic xlink:href="367_1260_F4"></graphic>
</fig>
<p>The rapid global spread of 2019-nCoV, which prompted the PHEIC declaration by WHO, signals
the urgent need for coronavirus vaccines and therapeutics. Knowing the atomic-level structure
of the 2019-nCoV spike will allow for additional protein-engineering efforts that could
improve antigenicity and protein expression for vaccine development. The structural data will
also facilitate the evaluation of 2019-nCoV spike mutations that will occur as the virus
undergoes genetic drift and help to define whether those residues have surface exposure and
map to sites of known antibody epitopes for other coronavirus spike proteins. In addition, the
structure provides assurance that the protein produced by this construct is homogeneous and in
the prefusion conformation, which should maintain the most neutralization-sensitive epitopes
when used as candidate vaccine antigens or B cell probes for isolating neutralizing human
mAbs. Furthermore, the atomic-level detail will enable the design and screening of small
molecules with fusion-inhibiting potential. This information will support precision vaccine
design and the discovery of antiviral therapeutics, accelerating medical countermeasure
development.</p>
</body>
<back><ack><title>Acknowledgments</title>
<p>We thank J. Ludes-Meyers for assistance with cell transfection, members of the McLellan
laboratory for critical reading of the manuscript, and A. Dai from the Sauer Structural
Biology Laboratory at the University of Texas at Austin for assistance with microscope
alignment. <bold>Funding:</bold>
This work was supported in part by a National Institutes of
Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant awarded to
J.S.M. (R01-AI127521) and by intramural funding from NIAID to B.S.G. The Sauer Structural
Biology Laboratory is supported by the University of Texas College of Natural Sciences and
by award RR160023 from the Cancer Prevention and Research Institute of Texas (CPRIT).
<bold>Author contributions:</bold>
D.W. collected and processed cryo-EM data. D.W., N.W.,
and J.S.M. built and refined the atomic model. N.W. designed and cloned all constructs.
D.W., N.W., K.S.C., J.A.G., and O.A. expressed and purified proteins. D.W., J.A.G., and
C.-L.H. performed binding studies. B.S.G. and J.S.M. supervised experiments. D.W., B.S.G.,
and J.S.M. wrote the manuscript with input from all authors. <bold>Competing
interests:</bold>
N.W., K.S.C., B.S.G., and J.S.M. are inventors on U.S. patent
application no. 62/412,703 (“Prefusion Coronavirus Spike Proteins and Their
Use”), and D.W., N.W., K.S.C., O.A., B.S.G., and J.S.M. are inventors on U.S. patent
application no. 62/972,886 (“2019-nCoV Vaccine”). <bold>Data and materials
availability:</bold>
Atomic coordinates and cryo-EM maps of the reported structure have
been deposited in the Protein Data Bank under accession code 6VSB and in the Electron
Microscopy Data Bank under accession codes EMD-21374 and EMD-21375. Plasmids are available
from B.S.G. under a material transfer agreement with the NIH or from J.S.M. under a material
transfer agreement with The University of Texas at Austin.</p>
</ack>
<app-group><app><title>Supplementary Material</title>
<supplementary-material content-type="local-data"><p><ext-link ext-link-type="uri" xlink:href="http://science.sciencemag.org/content/367/6483/1260/suppl/DC1">science.sciencemag.org/content/367/6483/1260/suppl/DC1</ext-link>
</p>
<p>Materials and Methods</p>
<p>Figs S1 to S8</p>
<p>Table S1</p>
<p>Movies S1 and S2</p>
<p>References (<xref rid="R32" ref-type="bibr"><italic>32</italic>
</xref>
–<xref rid="R41" ref-type="bibr"><italic>41</italic>
</xref>
)</p>
<p>MDAR Reproducibility Checklist</p>
</supplementary-material>
<supplementary-material content-type="local-data" id="S1"><media xlink:href="abb2507_Reproducibility_Checklist.pdf"><caption><p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
<supplementary-material content-type="local-data" id="S2"><media xlink:href="abb2507-Wrapp-SM.pdf"><caption><p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
<supplementary-material content-type="local-data" id="S3"><media xlink:href="abb2507s1.mov"><caption><p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
<supplementary-material content-type="local-data" id="S4"><media xlink:href="abb2507s2.mov"><caption><p>Click here for additional data file.</p>
</caption>
</media>
</supplementary-material>
</app>
<app><p><ext-link ext-link-type="uri" xlink:href="https://en.bio-protocol.org/cjrap.aspx?eid=10.1126/science.abb2507">View/request a protocol for this paper from
<italic>Bio-protocol</italic>
</ext-link>
.</p>
</app>
</app-group>
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