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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory
Syndrome Coronavirus<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Wu, Kailang" sort="Wu, Kailang" uniqKey="Wu K" first="Kailang" last="Wu">Kailang Wu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Peng, Guiqing" sort="Peng, Guiqing" uniqKey="Peng G" first="Guiqing" last="Peng">Guiqing Peng</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Wilken, Matthew" sort="Wilken, Matthew" uniqKey="Wilken M" first="Matthew" last="Wilken">Matthew Wilken</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation><nlm:aff id="aff2">Center for Drug Design, University of Minnesota Medical School, Minneapolis, Minnesota 55455</nlm:aff></affiliation></author><author><name sortKey="Li, Fang" sort="Li, Fang" uniqKey="Li F" first="Fang" last="Li">Fang Li</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22291007</idno><idno type="pmc">3308800</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308800</idno><idno type="RBID">PMC:3308800</idno><idno type="doi">10.1074/jbc.M111.325803</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001111</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001111</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory
Syndrome Coronavirus<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Wu, Kailang" sort="Wu, Kailang" uniqKey="Wu K" first="Kailang" last="Wu">Kailang Wu</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Peng, Guiqing" sort="Peng, Guiqing" uniqKey="Peng G" first="Guiqing" last="Peng">Guiqing Peng</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Wilken, Matthew" sort="Wilken, Matthew" uniqKey="Wilken M" first="Matthew" last="Wilken">Matthew Wilken</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Geraghty, Robert J" sort="Geraghty, Robert J" uniqKey="Geraghty R" first="Robert J." last="Geraghty">Robert J. Geraghty</name><affiliation><nlm:aff id="aff2">Center for Drug Design, University of Minnesota Medical School, Minneapolis, Minnesota 55455</nlm:aff></affiliation></author><author><name sortKey="Li, Fang" sort="Li, Fang" uniqKey="Li F" first="Fang" last="Li">Fang Li</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Biological Chemistry</title><idno type="ISSN">0021-9258</idno><idno type="eISSN">1083-351X</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Background:</bold> The severe acute respiratory syndrome (SARS) virus has
undergone mutations in its receptor-binding domain.</p><p><bold>Results:</bold> We used biochemical, functional, and crystallographic
methods to investigate these mutations.</p><p><bold>Conclusion:</bold> These mutations were viral adaptations to either the
human or palm civet receptor.</p><p><bold>Significance:</bold> This research elucidates detailed mechanisms of host
receptor adaptation by the SARS virus and can help predict and monitor future
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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Biol Chem</journal-id><journal-id journal-id-type="iso-abbrev">J. Biol. Chem</journal-id><journal-id journal-id-type="publisher-id">J. Biol. Chem</journal-id><journal-id journal-id-type="hwp">jbc</journal-id><journal-id journal-id-type="pmc">jbc</journal-id><journal-id journal-id-type="publisher-id">JBC</journal-id><journal-title-group><journal-title>The Journal of Biological Chemistry</journal-title></journal-title-group><issn pub-type="ppub">0021-9258</issn><issn pub-type="epub">1083-351X</issn><publisher><publisher-name>American Society for Biochemistry and Molecular
Biology</publisher-name><publisher-loc>9650 Rockville Pike, Bethesda, MD 20814, U.S.A.</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22291007</article-id><article-id pub-id-type="pmc">3308800</article-id><article-id pub-id-type="publisher-id">M111.325803</article-id><article-id pub-id-type="doi">10.1074/jbc.M111.325803</article-id><article-categories><subj-group subj-group-type="heading"><subject>Microbiology</subject></subj-group></article-categories><title-group><article-title>Mechanisms of Host Receptor Adaptation by Severe Acute Respiratory
Syndrome Coronavirus<xref ref-type="fn" rid="FN1">*</xref><xref ref-type="fn" rid="FN2"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></article-title><alt-title alt-title-type="short">Evolution and Receptor Recognition of SARS
Virus</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Kailang</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN3"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peng</surname><given-names>Guiqing</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN3"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wilken</surname><given-names>Matthew</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="author-notes" rid="FN3"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Geraghty</surname><given-names>Robert J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>§</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Fang</given-names></name><xref ref-type="aff" rid="aff1"><sup>‡</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1">From the<label>‡</label>Department of Pharmacology and</aff><aff id="aff2"><label>§</label>Center for Drug Design, University of Minnesota Medical School, Minneapolis, Minnesota 55455</aff></contrib-group><author-notes><corresp id="cor1"><label>2</label> To whom correspondence should be addressed:
<addr-line>Dept. of Pharmacology, University of Minnesota Medical School,
6-121 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455.</addr-line>Tel.: <phone>612-625-6149</phone>; Fax: <fax>612-625-8408</fax>; E-mail:
<email>lifang@umn.edu</email>.</corresp><fn fn-type="equal" id="FN3"><label>1</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>16</day><month>3</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>30</day><month>1</month><year>2012</year></pub-date><volume>287</volume><issue>12</issue><fpage>8904</fpage><lpage>8911</lpage><history><date date-type="received"><day>21</day><month>11</month><year>2011</year></date><date date-type="rev-recd"><day>26</day><month>1</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 by The American Society for Biochemistry and
Molecular Biology, Inc.</copyright-statement><copyright-year>2012</copyright-year><license><license-p>This article is made available via the PMC Open Access Subset for
unrestricted re-use and analyses in any form or by any means with
acknowledgement of the original source. These permissions are granted for
the duration of the COVID-19 pandemic or until permissions are revoked in
writing. Upon expiration of these permissions, PMC is granted a perpetual
license to make this article available via PMC and Europe PMC, consistent
with existing copyright protections.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zbc01212008904.pdf"></self-uri><abstract abstract-type="teaser"><p><bold>Background:</bold> The severe acute respiratory syndrome (SARS) virus has
undergone mutations in its receptor-binding domain.</p><p><bold>Results:</bold> We used biochemical, functional, and crystallographic
methods to investigate these mutations.</p><p><bold>Conclusion:</bold> These mutations were viral adaptations to either the
human or palm civet receptor.</p><p><bold>Significance:</bold> This research elucidates detailed mechanisms of host
receptor adaptation by the SARS virus and can help predict and monitor future
evolution of the SARS virus in animals.</p></abstract><abstract><p>The severe acute respiratory syndrome coronavirus (SARS-CoV) from palm civets has
twice evolved the capacity to infect humans by gaining binding affinity for
human receptor angiotensin-converting enzyme 2 (ACE2). Numerous mutations have
been identified in the receptor-binding domain (RBD) of different SARS-CoV
strains isolated from humans or civets. Why these mutations were naturally
selected or how SARS-CoV evolved to adapt to different host receptors has been
poorly understood, presenting evolutionary and epidemic conundrums. In this
study, we investigated the impact of these mutations on receptor recognition, an
important determinant of SARS-CoV infection and pathogenesis. Using a
combination of biochemical, functional, and crystallographic approaches, we
elucidated the molecular and structural mechanisms of each of these naturally
selected RBD mutations. These mutations either strengthen favorable interactions
or reduce unfavorable interactions with two virus-binding hot spots on ACE2, and
by doing so, they enhance viral interactions with either human (hACE2) or civet
(cACE2) ACE2. Therefore, these mutations were viral adaptations to either hACE2
or cACE2. To corroborate the above analysis, we designed and characterized two
optimized RBDs. The human-optimized RBD contains all of the hACE2-adapted
residues (Phe-442, Phe-472, Asn-479, Asp-480, and Thr-487) and possesses
exceptionally high affinity for hACE2 but relative low affinity for cACE2. The
civet-optimized RBD contains all of the cACE2-adapted residues (Tyr-442,
Pro-472, Arg-479, Gly-480, and Thr-487) and possesses exceptionally high
affinity for cACE2 and also substantial affinity for hACE2. These results not
only illustrate the detailed mechanisms of host receptor adaptation by SARS-CoV
but also provide a molecular and structural basis for tracking future SARS-CoV
evolution in animals.</p></abstract><kwd-group><kwd>Crystallography</kwd><kwd>Evolution</kwd><kwd>Infectious Diseases</kwd><kwd>Receptors</kwd><kwd>Virus</kwd></kwd-group><funding-group><award-group><funding-source id="CS100">National Institutes of Health</funding-source><award-id rid="CS100">R01 AI089728</award-id></award-group></funding-group></article-meta></front><body><sec><title>Introduction</title><p>Many viruses, particularly RNA viruses, can rapidly adapt to changes in their hosts
due to the high mutation rates of these viruses. Such viral adaptation to hosts
imposes huge threats to human health because it allows viruses to emerge from
animals to infect humans. Understanding viral adaptation to hosts would allow humans
to track viral evolution that may lead to viral epidemics, but current knowledge of
the mechanisms of viral adaptation to hosts is limited. This study investigates the
mechanisms of host receptor adaptation by the severe acute respiratory syndrome
coronavirus (SARS-CoV),<xref ref-type="fn" rid="FN4"><sup>3</sup></xref> the agent
of the SARS epidemic, and provides a molecular and structural basis for monitoring
future SARS-CoV evolution in animals.</p><p>SARS broke out as a worldwide epidemic in 2002–2003, causing >8000
human infections with a 10% fatality rate (<xref rid="B1" ref-type="bibr">1</xref>–<xref rid="B4" ref-type="bibr">4</xref>). SARS briefly
recurred in 2003–2004, causing sporadic human infections with mild symptoms
and no human-to-human transmission (<xref rid="B5" ref-type="bibr">5</xref>–<xref rid="B7" ref-type="bibr">7</xref>). Since the SARS
epidemic, various SARS-CoV strains have been isolated from humans and palm civets
(see <xref ref-type="fig" rid="F1">Fig. 1</xref><italic>A</italic>). The prototypic
human strain, hTor02, was isolated during the 2002–2003 SARS epidemic (<xref rid="B8" ref-type="bibr">8</xref>). A strain common to humans and civets,
hcGd03, was isolated during the 2003–2004 sporadic SARS infections (<xref rid="B6" ref-type="bibr">6</xref>, <xref rid="B7" ref-type="bibr">7</xref>).
Strain cSz02 was isolated from civets in animal markets in southern China during the
SARS outbreak (<xref rid="B5" ref-type="bibr">5</xref>). Strain cHb05 was isolated
from wild civets in central China several years after the SARS outbreak (<xref rid="B9" ref-type="bibr">9</xref>). In addition, human strain hHae08 was
isolated after adaptation of SARS-CoV to human airway epithelial cells <italic>in
vitro</italic> (<xref rid="B10" ref-type="bibr">10</xref>). Because of the
extremely high genetic similarity (∼99%) between human and civet SARS-CoV,
it is believed that civets played a direct role in transmitting SARS-CoV to humans
and were responsible for both of the human SARS infections (<xref rid="B5" ref-type="bibr">5</xref>, <xref rid="B11" ref-type="bibr">11</xref>, <xref rid="B12" ref-type="bibr">12</xref>). Although SARS-like coronaviruses (SLCVs)
have been isolated from bats, the genetic difference between SLCVs and human or
civet SARS-CoV is much greater than that between human and civet SARS-CoV (<xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B14" ref-type="bibr">14</xref>).
Moreover, SLCVs cannot infect human or civet cells, and SARS-CoV cannot infect bats
(<xref rid="B15" ref-type="bibr">15</xref>). Because of the direct role of
civets in the past SARS epidemic, this study focused on SARS-CoV strains isolated
from humans and civets.</p><p>Receptor recognition is the first step in viral infection of host cells and one of
the most important determinants of viral infectivity and pathogenesis. Although many
other host and viral factors can also affect the efficiency of infection and
replication of a virus in a specific host, these factors come into play only after a
virus has bound to a receptor on the cell membrane. A trimeric spike protein on the
SARS-CoV envelope mediates viral entry into host cells. It first binds to its host
receptor, angiotensin-converting enzyme 2 (ACE2) (<xref rid="B16" ref-type="bibr">16</xref>), and subsequently fuses host and viral membranes (<xref rid="B17" ref-type="bibr">17</xref>–<xref rid="B19" ref-type="bibr">19</xref>). A defined receptor-binding domain (RBD) on the SARS-CoV spike
protein is sufficient for high-affinity binding to ACE2 (<xref rid="B20" ref-type="bibr">20</xref>–<xref rid="B22" ref-type="bibr">22</xref>). The
RBD/ACE2 binding affinity has been established as a key element of SARS-CoV
pathogenesis and cross-species infections (<xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B11" ref-type="bibr">11</xref>, <xref rid="B23" ref-type="bibr">23</xref>–<xref rid="B25" ref-type="bibr">25</xref>). The
crystal structure of hTor02 RBD complexed with human ACE2 (hACE2) showed that the
RBD contains two subdomains, a core structure and a receptor-binding motif (RBM)
that directly binds ACE2 (see <xref ref-type="fig" rid="F1">Fig.
1</xref><italic>B</italic>) (<xref rid="B26" ref-type="bibr">26</xref>). Using
hTor02 RBD as a reference, numerous naturally selected mutations have been
identified in the RBDs of different SARS-CoV strains isolated from humans or civets.
The majority of these mutations fall in the RBM region (see <xref ref-type="fig" rid="F1">Fig. 1</xref>, <italic>A</italic> and <italic>B</italic>). To date,
research has focused on two of these mutations, N479K and T487S (<xref rid="B7" ref-type="bibr">7</xref>, <xref rid="B11" ref-type="bibr">11</xref>,
<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B27" ref-type="bibr">27</xref>, <xref rid="B28" ref-type="bibr">28</xref>). Biochemical studies
showed that both mutations N479K and T487S significantly decrease the RBD/hACE2
binding affinity (<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B28" ref-type="bibr">28</xref>). Structural studies revealed that mutation N479K introduces
an energetically unfavorable positive charge at the RBD/hACE2 interface, whereas
mutation T487S removes an energetically favorable hydrophobic interaction with hACE2
Lys-353 (see <xref ref-type="fig" rid="F1">Fig. 1</xref><italic>C</italic>) (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>).
The molecular and structural mechanisms of all of the other RBM mutations are poorly
understood. It is not known why any of these RBM mutations were naturally selected
or which RBM mutations were viral adaptations to which host.</p><p>Here, we investigated the role of each of the RBM mutations in viral interactions
with hACE2 and civet ACE2 (cACE2) using a combination of biochemical, functional and
crystallographic methods. Our results show that all of the above RBM mutations were
viral adaptations to two “virus-binding hot spots” on ACE2 and
suggest that these mutations were naturally selected because they enhance viral
interactions with either hACE2 or cACE2. These detailed mechanisms allow us to
understand the events that led to the past SARS epidemic and to monitor the events
that may lead to future SARS epidemics.</p></sec><sec sec-type="methods"><title>EXPERIMENTAL PROCEDURES</title><sec><title></title><sec><title></title><sec><title>Protein Purification, Crystallization, and Structure
Determination</title><p>SARS-CoV RBDs (from different viral strains) and ACE2 peptidase domains
(human, civet, or chimeric) were expressed and purified as described
previously (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>). In brief, the proteins
containing an N-terminal honeybee melittin signal peptide and a
C-terminal His tag were expressed in Sf9 insect cells using the
Bac-to-Bac system (Invitrogen). The proteins were harvested from Sf9
cell supernatants and purified sequentially on a nickel-nitrilotriacetic
acid column and a Superdex 200 gel filtration column (GE Healthcare). To
purify the RBD-ACE2 complex, ACE2 was incubated with excess RBD, and
then the complex was purified by gel filtration chromatography. RBD-ACE2
crystals were grown in sitting drops at room temperature over wells
containing 100 m<sc>m</sc> Tris (pH 8.5), 20–24% PEG 6000, and
100 m<sc>m</sc> NaCl. Crystals were soaked briefly in 100 m<sc>m</sc>Tris (pH 8.5), 30% PEG 6000, 100 m<sc>m</sc> NaCl, and 30% ethylene
glycol before being flash-frozen in liquid nitrogen. X-ray diffraction
data were collected at Argonne Photon Source beamlines 19-ID and 24-ID
and Advanced Light Source beamline 4.2.2. Each structure was determined
by molecular replacement using the structure of hACE2 complexed with
hTor02 RBD as the search model (Protein Data Bank code <ext-link ext-link-type="pdb" xlink:href="2AJF">2AJF</ext-link>). Data and
refinement statistics are shown in <xref rid="T1" ref-type="table">Table
1</xref>. The software used for data processing and structure
refinement is also listed in <xref rid="T1" ref-type="table">Table
1</xref>.</p></sec><sec><title>RBD/hACE2 Binding Assays</title><p>Surface plasmon resonance assays using a Biacore 2000 system were carried
out as described previously (<xref rid="B29" ref-type="bibr">29</xref>,
<xref rid="B30" ref-type="bibr">30</xref>). In brief, to measure the
binding affinities between mutant viral RBDs and wild-type ACE2, ACE2
was immobilized on a C5 sensor chip through direct covalent coupling via
amine groups, and soluble RBDs were introduced at a flow rate of 20
μl/min at different concentrations (62.5, 125, and 250
n<sc>m</sc>). To measure the binding affinities between mutant ACE2
and wild-type viral RBDs, RBDs were immobilized on the sensor chip, and
ACE2 was flowed through.</p></sec><sec><title>Pseudotyped Viral Infection Assays</title><p>Infection was assayed using murine leukemia viruses expressing
β-galactosidase and pseudotyped with SARS-CoV spike protein as
described previously (<xref rid="B29" ref-type="bibr">29</xref>). In
brief, to prepare pseudotyped viruses, HEK293T cells were cotransfected
with spike protein-encoding pcDNA3.1, p3240 expressing murine leukemia
virus <italic>gag</italic> and <italic>pol</italic> genes, and a murine
leukemia virus β-galactosidase-transducing vector (pBAG) (<xref rid="B31" ref-type="bibr">31</xref>). Viral supernatants were
harvested and inoculated on HEK293T cells expressing ACE2 in pcDNA3.1.
Infection efficiency was quantified by measuring β-galactosidase
activity. The spike proteins and ACE2 contained a C-terminal C9 tag and
HA tag, respectively. Hence, the concentrations of the spike protein
packaged in pseudotyped viruses and of ACE2 expressed on the HEK293T
cell surface were detected by Western blotting using anti-C9 and anti-HA
antibodies, respectively, and quantified using ImageJ software (version
1.6) (<ext-link ext-link-type="uri" xlink:href="http://www.jbc.org/cgi/content/full/M111.325803/DC1">supplemental Fig. S1</ext-link>). Compared with the infection
experiments using fluorescence assays (<xref rid="B32" ref-type="bibr">32</xref>), the β-galactosidase assays used in this study
are not as sensitive but are more stable and repeatable.</p></sec></sec></sec></sec><sec><title>RESULTS AND DISCUSSIONS</title><sec><title></title><sec><title></title><sec><title>Two Virus-binding Hot Spots on hACE2</title><p>All of the RBM mutations cluster around two virus-binding hot spots on
hACE2, hot spot-31 and hot spot-353, which center on Lys-31 and Lys-353,
respectively (<xref ref-type="fig" rid="F1">Fig.
1</xref><italic>C</italic>). Hot spot-353 is recognized by both
SARS-CoV and human NL63 coronavirus, despite the markedly different
structures of their RBDs (<xref rid="B29" ref-type="bibr">29</xref>,
<xref rid="B30" ref-type="bibr">30</xref>). Hot spot-31 is
recognized by SARS-CoV only but not by NL63 coronavirus. The two hot
spots have both structural similarities and dissimilarities. In unbound
hACE2, both Lys-31 and Lys-353 point away from the protein and into
solution (<xref rid="B33" ref-type="bibr">33</xref>). Upon SARS-CoV
binding, both residues fold back, become buried in hydrophobic
environments, and form salt bridges with hACE2 Glu-35 and Asp-38,
respectively (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>). Because of the hydrophobic
environments, formation of the salt bridges provides significant amounts
of energy to the virus/receptor interactions. The difference between the
two hot spots is that, upon salt bridge formation, Lys-353 is in a
relatively extended conformation that is energetically favorable,
whereas Lys-31 is in a strained conformation that is energetically
unfavorable. In this study, we examined the structure and function of
hot spot-31 by mutagenesis using surface plasmon resonance Biacore
assays and pseudotyped viral infection assays (<xref ref-type="fig" rid="F2">Fig. 2</xref>, <italic>A</italic> and <italic>B</italic>).
Both assays showed that mutation K31A did not have a significant impact
on RBD/hACE2 binding (<italic>p</italic> > 0.10
(<italic>t</italic> test) for both <italic>K<sub>a</sub></italic>and infection). In contrast, mutation K353A significantly decreased
RBD/hACE2 binding affinity (<italic>p</italic> < 0.01 for both
<italic>K<sub>a</sub></italic> and infection). These results
suggest that there was a significant net energy gain from salt bridge
formation at hot spot-353. In contrast, there was no significant net
energy gain from salt bridge formation at hot spot-31, as the energy
gain from salt bridge formation was cancelled out by loss from the
strained conformation of Lys-31.</p><fig id="F1" orientation="portrait" position="float"><label>FIGURE 1.</label><caption><p><bold>Interface between SARS-CoV RBD and hACE2.</bold><italic>A</italic>, list of mutations in the RBMs of various
SARS-CoV strains. Five representative existent strains and two
predicted future strains are defined in the Introduction.
<italic>B</italic>, overall structure of the hTor02
RBD-hACE2 complex (Protein Data Bank code <ext-link ext-link-type="pdb" xlink:href="2AJF">2AJF</ext-link>).
hACE2 is in <italic>green</italic>, and hTor02 RBD is in
<italic>cyan</italic> (core) and <italic>red</italic> (RBM).
RBM residues that underwent mutations are displayed.
<italic>C</italic>, detailed structure of the hTor02
RBD/hACE2 interface. hACE2 residues are in
<italic>green</italic>, SARS-CoV residues that underwent
mutations are in <italic>magenta</italic>, and SARS-CoV residues
that played significant roles in the mutations are in
<italic>cyan</italic>.</p></caption><graphic xlink:href="zbc0141201540001"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>FIGURE 2.</label><caption><p><bold>Structures and functions of two virus-binding hot spots on
hACE2.</bold><italic>A</italic>, surface plasmon resonance Biacore analysis
of the binding interactions between hTor02 RBD and wild-type or
mutant hACE2. hTor02 RBD was immobilized, and wild-type or
mutant ACE2 was flowed through. Each experiment was repeated six
times at three different protein concentrations. The
corresponding S.E. values are shown. <italic>B</italic>,
pseudotyped viral infection assays of the interactions between
hTor02 spike protein and wild-type or mutant hACE2. Retroviral
murine leukemia viruses expressing β-galactosidase and
pseudotyped with hTor02 spike protein were used to infect
HEK293T cells expressing wild-type or mutant hACE2. Infection
efficiency of pseudotyped viruses was measured by
β-galactosidase assays and normalized against the
infection efficiency in cells expressing wild-type hACE2. Each
experiment was repeated six times. The corresponding S.E. values
are shown. <italic>C</italic>, use of a human-civet chimeric
ACE2 in crystallographic studies of RBD/cACE2 interactions. The
chimeric ACE2 contains SARS-CoV-binding residues from cACE2 and
other residues from hACE2. The chimeric ACE2 has the same
receptor activities as cACE2 but the same crystallographic
activities as hACE2 (<xref rid="B27" ref-type="bibr">27</xref>).
SARS-CoV-binding residues that differ between hACE2 and cACE2
are shown. <italic>D</italic>, structure of the interface
between hTor02 RBD and the chimeric ACE2.</p></caption><graphic xlink:href="zbc0141201540002"></graphic></fig><p>To further understand the structure and function of hot spot-31, we
investigated mutation K31T in hACE2 based on the observation that cACE2,
containing Thr-31, is an efficient receptor for hTor02 (<xref ref-type="fig" rid="F2">Fig. 2</xref><italic>C</italic>). Both
Biacore and pseudotyped viral infection assays showed that mutation K31T
significantly increased RBD/hACE2 binding affinity (<italic>p</italic>< 0.001 for both <italic>K<sub>a</sub></italic> and infection)
(<xref ref-type="fig" rid="F2">Fig. 2</xref>, <italic>A</italic> and
<italic>B</italic>). To investigate the structural basis for
mutation K31T, we determined the crystal structure of a human-civet
chimeric ACE2 complexed with hTor02 RBD (<xref rid="T1" ref-type="table">Table 1</xref>). The chimeric ACE2 contained SARS-CoV-binding
residues from cACE2 (<xref ref-type="fig" rid="F2">Fig.
2</xref><italic>C</italic>) and other residues from hACE2. We
previously established this chimeric ACE2 as a useful alternative to
cACE2 in crystallographic analysis of SARS-CoV/cACE2 interactions by
showing that the chimeric ACE2 had the same receptor activities as cACE2
but the same crystallographic activities as hACE2 (<xref rid="B27" ref-type="bibr">27</xref>). The structure of the hTor02 RBD-chimeric ACE2
complex showed that a hydrogen bond between chimeric ACE2 Thr-31 and RBD
Tyr-442 strengthens a hydrophobic network around hot spot-31 at the
virus/receptor interface (<xref ref-type="fig" rid="F2">Fig.
2</xref><italic>D</italic>). Therefore, despite its insignificant
net energy contribution, hot spot-31 plays an important role in RBD/ACE2
interactions. Consequently, upon introduction to a new species, SARS-CoV
RBD may need to adapt to both hot spot-31 and hot spot-353 on ACE2.</p><table-wrap id="T1" orientation="portrait" position="float"><label>TABLE 1</label><caption><p><bold>Crystallographic data collection and refinement
statistics</bold></p><p>X-ray diffraction data were processed using HKL2000 (<xref rid="B35" ref-type="bibr">35</xref>). Programs CNS (<xref rid="B36" ref-type="bibr">36</xref>) and CCP4 REFMAC (<xref rid="B37" ref-type="bibr">37</xref>) were used for structure
refinement. Structural illustrations were made using POVscript
(<xref rid="B38" ref-type="bibr">38</xref>). r.m.s.d., root
mean square deviation.</p></caption><table frame="hsides" rules="groups"><thead valign="bottom"><tr><th rowspan="2" colspan="1"></th><th align="center" colspan="4" rowspan="1">Complex<hr></hr></th></tr><tr><th align="center" rowspan="1" colspan="1">hTor02
RBD-chimeric ACE2</th><th align="center" rowspan="1" colspan="1">hOptimize
RBD-hACE2</th><th align="center" rowspan="1" colspan="1">cOptimize
RBD-chimeric ACE2</th><th align="center" rowspan="1" colspan="1">cOptimize
RBD-hACE2</th></tr></thead><tbody valign="top"><tr><td align="left" rowspan="1" colspan="1"><bold>Data</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Space group</td><td align="left" rowspan="1" colspan="1">P2<sub>1</sub></td><td align="left" rowspan="1" colspan="1">P2<sub>1</sub></td><td align="left" rowspan="1" colspan="1">P2<sub>1</sub></td><td align="left" rowspan="1" colspan="1">P2<sub>1</sub></td></tr><tr><td align="left" rowspan="1" colspan="1"> Cell constants</td><td align="left" rowspan="1" colspan="1"><italic>a</italic>= 81.6, <italic>b</italic> = 119.5, <italic>c</italic> =
113.4 Å; β = 92.5º</td><td align="left" rowspan="1" colspan="1"><italic>a</italic>= 81.4, <italic>b</italic> = 118.3, <italic>c</italic> =
111.9 Å; β = 93.15º</td><td align="left" rowspan="1" colspan="1"><italic>a</italic>= 81.0, <italic>b</italic> = 120.0, <italic>c</italic> =
112.2 Å; β = 93.15º</td><td align="left" rowspan="1" colspan="1"><italic>a</italic>= 81.2, <italic>b</italic> = 119.3, <italic>c</italic> =
113.2 Å; β = 92.25º</td></tr><tr><td align="left" rowspan="1" colspan="1"> Resolution
(Å)</td><td align="left" rowspan="1" colspan="1">50–3.0</td><td align="left" rowspan="1" colspan="1">50–2.9</td><td align="left" rowspan="1" colspan="1">50–3.0</td><td align="left" rowspan="1" colspan="1">50–3.0</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>R</italic><sub>sym</sub>(last shell) (%)</td><td align="left" rowspan="1" colspan="1">9.8 (61.6)</td><td align="left" rowspan="1" colspan="1">7.5 (33.4)</td><td align="left" rowspan="1" colspan="1">7.0 (51.6)</td><td align="left" rowspan="1" colspan="1">9.2 (48.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Observed
reflections</td><td align="left" rowspan="1" colspan="1">157,444</td><td align="left" rowspan="1" colspan="1">223,385</td><td align="left" rowspan="1" colspan="1">122,747</td><td align="left" rowspan="1" colspan="1">296,564</td></tr><tr><td align="left" rowspan="1" colspan="1"> Unique
reflections</td><td align="left" rowspan="1" colspan="1">42,738</td><td align="left" rowspan="1" colspan="1">47,509</td><td align="left" rowspan="1" colspan="1">42,870</td><td align="left" rowspan="1" colspan="1">44,284</td></tr><tr><td align="left" rowspan="1" colspan="1"> Completeness (last
shell) (%)</td><td align="left" rowspan="1" colspan="1">97.7 (95.1)</td><td align="left" rowspan="1" colspan="1">93.4 (59.1)</td><td align="left" rowspan="1" colspan="1">91.7 (59.9)</td><td align="left" rowspan="1" colspan="1">95.1 (67.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>I</italic>/σ
(last shell)</td><td align="left" rowspan="1" colspan="1">6.3 (1.2)</td><td align="left" rowspan="1" colspan="1">11.4 (3.2)</td><td align="left" rowspan="1" colspan="1">16.5 (1.6)</td><td align="left" rowspan="1" colspan="1">20.2 (2.2)</td></tr><tr><td colspan="5" rowspan="1"><hr></hr></td></tr><tr><td align="left" rowspan="1" colspan="1"><bold>Refinement</bold></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>R</italic><sub>work</sub>(<italic>R</italic><sub>free</sub>) (%)</td><td align="left" rowspan="1" colspan="1">23.9 (29.2)</td><td align="left" rowspan="1" colspan="1">22.6 (28.3)</td><td align="left" rowspan="1" colspan="1">23.9 (28.5)</td><td align="left" rowspan="1" colspan="1">23.0 (27.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"> <italic>R</italic><sub>free</sub>reflections (%)</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">5</td></tr><tr><td align="left" rowspan="1" colspan="1"> Bond length
r.m.s.d. (Å)</td><td align="left" rowspan="1" colspan="1">0.012</td><td align="left" rowspan="1" colspan="1">0.010</td><td align="left" rowspan="1" colspan="1">0.011</td><td align="left" rowspan="1" colspan="1">0.010</td></tr><tr><td align="left" rowspan="1" colspan="1"> Bond angle
r.m.s.d.</td><td align="left" rowspan="1" colspan="1">1.361º</td><td align="left" rowspan="1" colspan="1">1.252º</td><td align="left" rowspan="1" colspan="1">1.329º</td><td align="left" rowspan="1" colspan="1">1.257º</td></tr><tr><td align="left" rowspan="1" colspan="1"> Chiral r.m.s.d.
(Å<sup>3</sup>)</td><td align="left" rowspan="1" colspan="1">0.092</td><td align="left" rowspan="1" colspan="1">0.090</td><td align="left" rowspan="1" colspan="1">0.086</td><td align="left" rowspan="1" colspan="1">0.083</td></tr></tbody></table></table-wrap></sec><sec><title>Molecular Mechanisms of RBM Mutations in SARS-CoV</title><p>To investigate the molecular mechanisms of the RBM mutations, we
introduced seven single mutations to hTor02 RBD, Y442F, L472P, L472F,
N479K, N479R, D480G, and T487S, corresponding to all of the RBM
mutations identified in human and civet SARS-CoV strains (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>A</italic>). We
expressed and purified each of these mutant RBDs and measured their
binding affinities for hACE2 and cACE2 using Biacore assays (<xref ref-type="fig" rid="F3">Fig. 3</xref>, <italic>A</italic> and
<italic>B</italic>). The results showed that hTor02 RBD bound to
hACE2 and cACE2 with similar <italic>K<sub>a</sub></italic> values
(<italic>p</italic> > 0.50). The affinity of hTor02 RBD for
hACE2 was increased by Y442F and L472F (<italic>p</italic> <
0.01); unchanged by N479R (<italic>p</italic> > 0.10); and
decreased by L472P, D480G, N479K, and T487S (<italic>p</italic>< 0.02) (<xref ref-type="fig" rid="F3">Fig.
3</xref><italic>A</italic>). The affinity of hTor02 RBD for cACE2
was increased by N479R and D480G (<italic>p</italic> < 0.01);
unchanged by L472P and N479K (<italic>p</italic> > 0.50); and
decreased by L472F, Y442F, and T487S (<italic>p</italic> < 0.01)
(<xref ref-type="fig" rid="F3">Fig. 3</xref><italic>B</italic>). In
sum, among the RBM residues that have been identified in different
SARS-CoV strains, Phe-442, Phe-472, Asn-479/Arg-479, Asp-480, and
Thr-487 enhanced RBD/hACE2 interactions, whereas Tyr-442,
Pro-472/Leu-472, Arg-479, Gly-480 and Thr-487 enhanced RBD/cACE2
interactions.</p><fig id="F3" orientation="portrait" position="float"><label>FIGURE 3.</label><caption><p><bold>Molecular mechanisms of RBM mutations in SARS-CoV.</bold><italic>A</italic>, surface plasmon resonance Biacore analysis
of the binding interactions between hACE2 and wild-type or
mutant hTor02 RBD. hACE2 was immobilized, and wild-type or
mutant hTor02 RBD was flowed through. <italic>B</italic>,
surface plasmon resonance Biacore analysis of the binding
interactions between cACE2 and wild-type or mutant hTor02 RBD.
cACE2 was immobilized, and wild-type or mutant hTor02 RBD was
flowed through. <italic>C</italic>, pseudotyped viral infection
assays of the interactions between different spike proteins and
hACE2. <italic>D</italic>, pseudotyped viral infection assays of
the interactions between different spike proteins and cACE2.</p></caption><graphic xlink:href="zbc0141201540003"></graphic></fig><p>The above results suggest that combinations of the RBM residues that
enhance RBD/hACE2 or RBD/cACE2 interactions can potentially produce new
RBDs with exceptionally high affinity for hACE2 or cACE2, respectively.
To test this hypothesis, we designed and constructed two such new RBDs:
hOptimize RBD containing Phe-442, Phe-472, Asn-479, Asp-480, and Thr-487
and cOptimize RBD containing Tyr-442, Pro-472, Arg-479, Gly-480, and
Thr-487 (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>A</italic>).
We expressed and purified each of the RBDs. Biacore assays confirmed
that compared with hTor02 RBD, hOptimize and cOptimize RBDs had higher
affinities for hACE2 and cACE2, respectively (<italic>p</italic>< 0.01) (<xref ref-type="fig" rid="F3">Fig. 3</xref>,
<italic>A</italic> and <italic>B</italic>). On the other hand,
whereas hOptimize RBD had low affinity for cACE2, cOptimize RBD had
substantial affinity for hACE2.</p></sec><sec><title>Structural Mechanisms of RBM Mutations in SARS-CoV</title><p>To investigate the structural mechanisms of the RBM mutations, we
determined the following three crystal structures: hOptimize RBD
complexed with hACE2, cOptimize RBD complexed with the chimeric ACE2,
and hOptimize RBD complexed with the chimeric ACE2 (<xref ref-type="fig" rid="F4">Fig. 4</xref> and <xref rid="T1" ref-type="table">Table
1</xref>). Together, these structures show that naturally selected
RBM mutations either strengthened favorable interactions or reduced
unfavorable interactions with the two virus-binding hot spots on ACE2.
The structural details of each of the RBM mutations are as follow.</p><fig id="F4" orientation="portrait" position="float"><label>FIGURE 4.</label><caption><p><bold>Structural mechanisms of RBM mutations in SARS-CoV.</bold><italic>A</italic>, structure of the interface between hACE2 and
hOptimize RBD. <italic>B</italic>, structure of the interface
between the chimeric ACE2 and cOptimize RBD. <italic>C</italic>,
structure of the interface between hACE2 and cOptimize RBD.
<italic>D</italic>, superimposed structures of the
interfaces between the chimeric ACE2 and cOptimize RBD
(<italic>colored</italic>) and between hACE2 and hTor02
(<italic>white</italic>).</p></caption><graphic xlink:href="zbc0141201540004"></graphic></fig><p>RBD residue 442 interacts with hot spot-31 on ACE2. At the RBD/hACE2
interfaces, the hydroxyl group of Tyr-442 has partial steric clash with
the alkyl side chain of hACE2 Lys-31 (<xref ref-type="fig" rid="F1">Fig.
1</xref><italic>C</italic>). Mutation Y442F removes this hydroxyl
group, partially releases the structural strain of Lys-31 (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>A</italic>), and
increases the RBD/hACE2 binding affinity. As discussed above, at the
RBD/chimeric ACE2 interfaces, the hydroxyl group of Tyr-442 forms a
critical hydrogen bond with chimeric ACE2 Thr-31 (<xref ref-type="fig" rid="F2">Figs. 2</xref><italic>D</italic> and <xref ref-type="fig" rid="F4">4</xref><italic>B</italic>). Mutation Y442F removes this
hydrogen bond, weakens the hydrophobic network around hot spot-31, and
decreases the RBD/cACE2 binding affinity. Therefore, Phe-442 and Tyr-442
were viral adaptations to hACE2 and cACE2, respectively (<xref ref-type="fig" rid="F5">Fig. 5</xref>).</p><fig id="F5" orientation="portrait" position="float"><label>FIGURE 5.</label><caption><p><bold>Summary of host receptor adaptation by SARS-CoV.</bold>Listed are adaptations of RBM residues to hACE2 or cACE2.
<italic>Arrows</italic> point from less well adapted
residues to better adapted residues. <italic>Double
arrows</italic> connect equally well adapted residues.</p></caption><graphic xlink:href="zbc0141201540005"></graphic></fig><p>RBD residue 472 interacts with hot spot-31 on ACE2. At the RBD/hACE2
interfaces, Leu-472 forms favorable hydrophobic interactions with hACE2
Met-82 and Leu-79 and strengthens the hydrophobic network around hot
spot-31 (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>C</italic>).
Mutation L472F further strengthens but mutation L472P weakens RBD/hACE2
interactions (<xref ref-type="fig" rid="F4">Fig. 4</xref>,
<italic>A</italic> and <italic>C</italic>). At the RBD/chimeric ACE2
interfaces, Phe-472 would have partial steric clash with the hydroxyl
group of chimeric ACE2 Thr-82 (<xref ref-type="fig" rid="F2">Figs.
2</xref><italic>D</italic> and <xref ref-type="fig" rid="F4">4</xref><italic>B</italic>), and hence, mutation L472F decreases
the RBD/cACE2 binding affinity. Additionally, neither Leu-472 nor
Pro-472 has significant contact with Thr-82 (<xref ref-type="fig" rid="F2">Figs. 2</xref><italic>D</italic> and <xref ref-type="fig" rid="F4">4</xref><italic>B</italic>), and hence, mutation L472P has
no significant effects on the RBD/cACE2 interactions. Therefore, Phe-472
and Pro-472/Leu-472 were viral adaptations to hACE2 and cACE2,
respectively (<xref ref-type="fig" rid="F5">Fig. 5</xref>).</p><p>RBD residue 479 interacts with both hot spots on ACE2. As shown
previously, at the RBD/hACE2 interfaces, mutation N479K introduces a
positive charge that can compete with hACE2 Lys-31 for hACE2 Glu-35 as a
salt bridge partner (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>), and hence, it decreases the
RBD/hACE2 binding affinity. Unexpectedly, unlike N479K, mutation N479R
has no significant effects on the RBD/hACE2 binding affinity even though
it does introduce a positive charge. This is because Arg-479 and hACE2
Lys-353 can both form a salt bridge with hACE2 Asp-38 (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>C</italic>). At the
RBD/chimeric ACE2 interfaces, Thr-31 cannot form a salt bridge with
chimeric ACE2 Glu-35 (<xref ref-type="fig" rid="F2">Figs.
2</xref><italic>D</italic> and <xref ref-type="fig" rid="F4">4</xref><italic>B</italic>), and hence, Glu-35 is available to form
a salt bridge with Lys-479. On the other hand, Lys-479 has high
conformational entropy and stacks poorly with the hydrophobic network
around hot spot-31 (<xref rid="B27" ref-type="bibr">27</xref>).
Consequently, mutation N479K has no significant effects on the RBD/cACE2
binding affinity. In contrast, Arg-479 can form a strong bifurcated salt
bridge with Glu-35 and is also a much better hydrophobic stacker than
Lys-479 (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>B</italic>).
Thus, mutation N479R increases the RBD/cACE2 binding affinity.
Therefore, Asn-479/Arg-479 and Arg-479 were viral adaptations to hACE2
and cACE2, respectively (<xref ref-type="fig" rid="F5">Fig.
5</xref>).</p><p>RBD residue 480 interacts with hot spot-353 on ACE2. At the RBD/hACE2
interfaces, RBD Tyr-436 forms a hydrogen bond with hACE2 Asp-38 and
strengthens the Lys-353–Asp-38 salt bridge (<xref ref-type="fig" rid="F1">Figs. 1</xref><italic>C</italic> and <xref ref-type="fig" rid="F4">4</xref><italic>D</italic>). The alkyl side chain of
Asp-480 forms a hydrophobic interaction with Tyr-436 and supports the
Tyr-436–Asp-38 hydrogen bond. Consequently, mutation D480G
weakens the above interactions and decreases the RBD/hACE2 binding
affinity. At the RBD/chimeric ACE2 interfaces, chimeric ACE2 Glu-38,
which has a longer side chain than hACE2 Asp-38, moves back to keep the
salt bridge with Lys-353. Accordingly, Tyr-436 also needs to move to
keep the hydrogen bond with Glu-38 (<xref ref-type="fig" rid="F4">Fig.
4</xref><italic>D</italic>). Mutation D480G facilitates the movement
of Tyr-436 and increases the RBD/cACE2 binding affinity. Therefore,
Asp-480 and Gly-480 were viral adaptations to hACE2 and cACE2,
respectively (<xref ref-type="fig" rid="F5">Fig. 5</xref>).</p><p>RBD residue 487 interacts with hot spot-353 on hACE2. As shown
previously, at the RBD/hACE2 interfaces, the methyl group of Thr-487
supports the Lys-353–Asp-38 salt bridge (<xref ref-type="fig" rid="F1">Fig. 1</xref><italic>C</italic>) (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B27" ref-type="bibr">27</xref>), and
hence, mutation T487S decreases the RBD/hACE2 binding affinity. At the
RBD/chimeric ACE2 interfaces, the methyl group of Thr-487 also supports
the Lys-353–Glu-38 salt bridge (<xref ref-type="fig" rid="F4">Fig. 4</xref><italic>B</italic>), and thus, mutation T487S
decreases the RBD/cACE2 binding affinity. Therefore, Thr-487 was a viral
adaptation to both hACE2 and cACE2 (<xref ref-type="fig" rid="F5">Fig.
5</xref>).</p></sec><sec><title>Evaluation of Host Cell Infections Mediated by Different SARS-CoV
Spike Proteins</title><p>To further investigate the interactions between different RBDs and ACE2
from humans or civets, we measured the spike protein-mediated infection
of hACE2- or cACE2-expressing cells using pseudotyped viral infection
assays (<xref ref-type="fig" rid="F3">Fig. 3</xref>, <italic>C</italic>and <italic>D</italic>). Compared with Biacore assays that directly
measure binding interactions between monomeric RBD and monomeric ACE2 in
solution, pseudotyped infection assays measure binding interactions
between trimeric spike proteins on viral surfaces and monomeric ACE2 on
target cell surfaces. In addition, pseudotyped infection assays require
not only receptor binding but also membrane fusion and post-fusion steps
for reporter gene expression. Hence, pseudotyped infection assays
reflect more truthfully than Biacore assays on how the RBM mutations may
impact SARS-CoV infectivity and pathogenesis.</p><p>The spike proteins used in the assays share the same sequences as the
hTor02 spike protein except that their RBDs contain different
combinations of RBM residues (<xref ref-type="fig" rid="F1">Fig.
1</xref><italic>A</italic>). hOptimize spike protein mediated a
higher level of infection of hACE2-expressing cells than all other spike
proteins (<italic>p</italic> < 0.01) because its residues at
positions 442, 472, 479, 480, and 487 were all best adapted to hACE2
(<xref ref-type="fig" rid="F3">Fig. 3</xref><italic>C</italic>).
Particularly, hOptimize spike protein-pseudotyped viruses infected
hACE2-expressing cells about twice as efficiently as hTor02 spike
protein-pseudotyped viruses and ∼4-fold as efficiently as cSz02
spike protein-pseudotyped viruses. Additionally, hOptimize spike protein
mediated a lower level of infection of cACE2-expressing cells than all
other spike proteins except hHae08 (<italic>p</italic> < 0.01)
because its residues at four of the above positions, except position
487, were poorly adapted to cACE2. On the other hand, cOptimize spike
protein mediated a higher level of infection of cACE2-expressing cells
than all other spike proteins (<italic>p</italic> < 0.01)
because its residues at the above five positions were all best adapted
to cACE2 (<xref ref-type="fig" rid="F3">Fig.
3</xref><italic>D</italic>). Particularly, cOptimize spike
protein-pseudotyped viruses infected cACE2-expressing cells about twice
as efficiently as hTor02 spike protein-pseudotyped viruses and
∼7-fold as efficiently as hHae08 spike protein-pseudotyped
viruses. cOptimize spike protein also mediated a substantial level of
infection of hACE2-expressing cells, lower than hTor02 but significantly
higher than hcGd03 (<italic>p</italic> < 0.01), because its
residues at positions 479 and 487 were well adapted to hACE2, whereas
its residues at the other three positions were poorly adapted to hACE2.
Overall, the results from the pseudotyped infection assays correlate
well with those from Biacore data and structural analysis.</p></sec><sec><title>Monitoring Future SARS-CoV Evolution in Animals</title><p>SARS-CoV evolution in animals needs to be carefully monitored as a
preventive measure for potential future SARS epidemics. SARS-CoV was
found in wild civets in 2005 (<xref rid="B9" ref-type="bibr">9</xref>)
and can potentially cross the species barrier to infect humans again, as
it did as least twice before. Novel coronaviruses have been identified
in bats (<xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B14" ref-type="bibr">14</xref>), and some of these bat
coronaviruses may be transmitted to humans either directly or through
some intermediate animal hosts (<xref rid="B11" ref-type="bibr">11</xref>). SARS-CoV may also be misused as a bioweapon to infect
humans. Regardless of the circumstances under which SARS-CoV re-emerges,
understanding the mechanisms of its host receptor adaptation will be
crucial for dealing with its re-emergence.</p><p>In this study, we have identified RBM residues that are best adapted to
hACE2 or cACE2, and hence, these residues can be predictors of future
SARS-CoV evolution in animals. The elucidated receptor recognition
mechanisms by SARS-CoV can allow us to evaluate the potential epidemical
consequences of a future SARS-CoV strain simply by examining its genomic
sequence. For example, if a future SARS-CoV strain is isolated from
civets or humans, we will be able to evaluate the binding affinity
between its RBD and cACE2 or hACE2 based on its RBM sequences. More
specifically, if a future SARS-CoV strain contains a majority or all of
the cACE2-adapted RBM residues, it can potentially have high infectivity
for civet cells; if it contains a majority or all of the hACE2-adapted
RBM residues, it can potentially have high infectivity for human cells.
Moreover, the detailed interactions between SARS-CoV RBD and the two
virus-binding hot spots on ACE2 as elucidated in this study will help us
understand and evaluate new RBM mutations in future SARS-CoV strains
that are different from the previously identified RBM mutations. The
results from this study can also contribute to the monitoring and
control of SLCVs in bats by providing insights into how these bat
viruses may interact with the ACE2 molecules from bats, civets, humans,
or other animals (<xref rid="B27" ref-type="bibr">27</xref>, <xref rid="B34" ref-type="bibr">34</xref>). It should be noted that our
study did not include replication-competent viruses or animal models,
and thus, future studies will be required to establish the correlation
between optimized RBDs and infectivities of live SARS-CoV strains. To
conclude, given that SARS-CoV may still be evolving in civets and that
SLCVs are harbored by bats, it remains possible for SARS-CoV to
re-emerge into the human population through civets or other animals, but
we can be better prepared to prevent or handle future outbreaks of the
virus with improved understanding of the mechanisms for its host
receptor adaptation.</p></sec></sec></sec></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="PMC_1"><caption><title>Supplemental Data</title></caption><media mimetype="text" mime-subtype="html" xlink:href="supp_287_12_8904__index.html" orientation="portrait" xlink:type="simple" id="d35e1265" position="anchor"></media><media xlink:role="associated-file" mimetype="application" mime-subtype="pdf" xlink:href="supp_M111.325803_jbc.M111.325803-1.pdf" orientation="portrait" xlink:type="simple" id="d35e1266" position="anchor"></media></supplementary-material></sec></body><back><fn-group><fn fn-type="supported-by" id="FN1"><label>*</label><p>This work was supported, in whole or in part, by National Institutes of Health
Grant R01 AI089728 (to F. L.). This work was also supported by a University of
Minnesota Academic Health Center faculty research development grant (to F. L.)
and by a Minnesota Partnership for Biotechnology and Medical Genomics grant (to
the University of Minnesota).</p></fn><fn fn-type="supplementary-material" id="FN2"><label><inline-graphic xlink:href="sbox.jpg"></inline-graphic></label><p>This article contains <ext-link ext-link-type="uri" xlink:href="http://www.jbc.org/cgi/content/full/M111.325803/DC1">supplemental Fig. S1</ext-link>.</p></fn><fn fn-type="other"><p>The atomic coordinates and structure factors (codes <ext-link ext-link-type="uri" xlink:href="http://www.pdb.org/pdb/explore/explore.do?structureId=3SCI">3SCI</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.pdb.org/pdb/explore/explore.do?structureId=3SCJ">3SCJ</ext-link>, <ext-link ext-link-type="uri" xlink:href="http://www.pdb.org/pdb/explore/explore.do?structureId=3SCK">3SCK</ext-link>, and <ext-link ext-link-type="uri" xlink:href="http://www.pdb.org/pdb/explore/explore.do?structureId=3SCL">3SCL</ext-link>) have been deposited in the Protein Data Bank, Research
Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick,
NJ (<ext-link ext-link-type="uri" xlink:href="http://www.rcsb.org/">http://www.rcsb.org/</ext-link>).</p></fn></fn-group><fn-group content-type="abbreviations"><fn id="FN4"><label>3</label><p>The abbreviations used are: <def-list><def-item><term id="G1">SARS-CoV</term><def><p>severe acute respiratory syndrome coronavirus</p></def></def-item><def-item><term id="G2">SLCV</term><def><p>SARS-like coronavirus</p></def></def-item><def-item><term id="G3">ACE2</term><def><p>angiotensin-converting enzyme 2</p></def></def-item><def-item><term id="G4">hACE2</term><def><p>human ACE2</p></def></def-item><def-item><term id="G5">cACE2</term><def><p>civet ACE2</p></def></def-item><def-item><term id="G6">RBD</term><def><p>receptor-binding domain</p></def></def-item><def-item><term id="G7">RBM</term><def><p>receptor-binding motif.</p></def></def-item></def-list></p></fn></fn-group><ack><title>Acknowledgments</title><p>We thank Drs. Kathryn Holmes, Ralph Baric, Carrie Wilmot, and Yuhong Jiang for
discussion and comments and the staff at Argonne Photon Source beamlines 19-ID and
24-ID and at Advanced Light Source beamline 4.2.2 for assistance in data collection.
Computer resources were provided by the Basic Sciences Computing Laboratory of the
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