Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
Identifieur interne : 001470 ( Pmc/Corpus ); précédent : 001469; suivant : 001471Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
Auteurs : Renhong Yan ; Yuanyuan Zhang ; Yaning Li ; Lu Xia ; Yingying Guo ; Qiang ZhouSource :
- Science (New York, N.y.) [ 0036-8075 ] ; 2020.
Abstract
Scientists are racing to learn the secrets of severe acute respiratory
syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease
COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein
to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan
Url:
DOI: 10.1126/science.abb2762
PubMed: 32132184
PubMed Central: 7164635
Links to Exploration step
PMC:7164635Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Structural basis for the recognition of SARS-CoV-2 by full-length human
ACE2</title><author><name sortKey="Yan, Renhong" sort="Yan, Renhong" uniqKey="Yan R" first="Renhong" last="Yan">Renhong Yan</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yuanyuan" sort="Zhang, Yuanyuan" uniqKey="Zhang Y" first="Yuanyuan" last="Zhang">Yuanyuan Zhang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Li, Yaning" sort="Li, Yaning" uniqKey="Li Y" first="Yaning" last="Li">Yaning Li</name><affiliation><nlm:aff id="aff3">Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.</nlm:aff></affiliation></author><author><name sortKey="Xia, Lu" sort="Xia, Lu" uniqKey="Xia L" first="Lu" last="Xia">Lu Xia</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Guo, Yingying" sort="Guo, Yingying" uniqKey="Guo Y" first="Yingying" last="Guo">Yingying Guo</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Zhou, Qiang" sort="Zhou, Qiang" uniqKey="Zhou Q" first="Qiang" last="Zhou">Qiang Zhou</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">32132184</idno><idno type="pmc">7164635</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164635</idno><idno type="RBID">PMC:7164635</idno><idno type="doi">10.1126/science.abb2762</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">001470</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001470</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Structural basis for the recognition of SARS-CoV-2 by full-length human
ACE2</title><author><name sortKey="Yan, Renhong" sort="Yan, Renhong" uniqKey="Yan R" first="Renhong" last="Yan">Renhong Yan</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Zhang, Yuanyuan" sort="Zhang, Yuanyuan" uniqKey="Zhang Y" first="Yuanyuan" last="Zhang">Yuanyuan Zhang</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Li, Yaning" sort="Li, Yaning" uniqKey="Li Y" first="Yaning" last="Li">Yaning Li</name><affiliation><nlm:aff id="aff3">Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.</nlm:aff></affiliation></author><author><name sortKey="Xia, Lu" sort="Xia, Lu" uniqKey="Xia L" first="Lu" last="Xia">Lu Xia</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Guo, Yingying" sort="Guo, Yingying" uniqKey="Guo Y" first="Yingying" last="Guo">Yingying Guo</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author><author><name sortKey="Zhou, Qiang" sort="Zhou, Qiang" uniqKey="Zhou Q" first="Qiang" last="Zhou">Qiang Zhou</name><affiliation><nlm:aff id="aff1">Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</nlm:aff></affiliation></author></analytic><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></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>How SARS-CoV-2 binds to human cells</title><p>Scientists are racing to learn the secrets of severe acute respiratory
syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease
COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein
to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan <italic>et al.</italic>present the structure of human ACE2 in complex with a membrane protein that it chaperones,
B<sup>0</sup>AT1. In the context of this complex, ACE2 is a dimer. A further structure
shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that
it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures
provide a basis for the development of therapeutics targeting this crucial
interaction.</p><p><italic>Science</italic>, this issue p. <ext-link ext-link-type="doi" xlink:href="10.1126/science.abb2762">1444</ext-link></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zhu, N" uniqKey="Zhu N">N. Zhu</name></author><author><name sortKey="Zhang, D" uniqKey="Zhang D">D. Zhang</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W. Wang</name></author><author><name sortKey="Li, X" uniqKey="Li X">X. Li</name></author><author><name sortKey="Yang, B" uniqKey="Yang B">B. Yang</name></author><author><name sortKey="Song, J" uniqKey="Song J">J. Song</name></author><author><name sortKey="Zhao, X" uniqKey="Zhao X">X. Zhao</name></author><author><name sortKey="Huang, B" uniqKey="Huang B">B. Huang</name></author><author><name sortKey="Shi, W" uniqKey="Shi W">W. Shi</name></author><author><name sortKey="Lu, R" uniqKey="Lu R">R. Lu</name></author><author><name sortKey="Niu, P" uniqKey="Niu P">P. Niu</name></author><author><name sortKey="Zhan, F" uniqKey="Zhan F">F. Zhan</name></author><author><name sortKey="Ma, X" uniqKey="Ma X">X. Ma</name></author><author><name sortKey="Wang, D" uniqKey="Wang D">D. Wang</name></author><author><name sortKey="Xu, W" uniqKey="Xu W">W. Xu</name></author><author><name sortKey="Wu, G" uniqKey="Wu G">G. Wu</name></author><author><name sortKey="Gao, G F" uniqKey="Gao G">G. F. Gao</name></author><author><name sortKey="Tan, W" uniqKey="Tan W">W. Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, P" uniqKey="Zhou P">P. Zhou</name></author><author><name sortKey="Yang, X L" uniqKey="Yang X">X.-L. Yang</name></author><author><name sortKey="Wang, X G" uniqKey="Wang X">X.-G. Wang</name></author><author><name sortKey="Hu, B" uniqKey="Hu B">B. Hu</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L. Zhang</name></author><author><name sortKey="Zhang, W" uniqKey="Zhang W">W. Zhang</name></author><author><name sortKey="Si, H R" uniqKey="Si H">H.-R. Si</name></author><author><name sortKey="Zhu, Y" uniqKey="Zhu Y">Y. Zhu</name></author><author><name sortKey="Li, B" uniqKey="Li B">B. Li</name></author><author><name sortKey="Huang, C L" uniqKey="Huang C">C.-L. Huang</name></author><author><name sortKey="Chen, H D" uniqKey="Chen H">H.-D. Chen</name></author><author><name sortKey="Chen, J" uniqKey="Chen J">J. Chen</name></author><author><name sortKey="Luo, Y" uniqKey="Luo Y">Y. Luo</name></author><author><name sortKey="Guo, H" uniqKey="Guo H">H. Guo</name></author><author><name sortKey="Jiang, R D" uniqKey="Jiang R">R.-D. Jiang</name></author><author><name sortKey="Liu, M Q" uniqKey="Liu M">M.-Q. Liu</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y. Chen</name></author><author><name sortKey="Shen, X R" uniqKey="Shen X">X.-R. Shen</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X. Wang</name></author><author><name sortKey="Zheng, X S" uniqKey="Zheng X">X.-S. Zheng</name></author><author><name sortKey="Zhao, K" uniqKey="Zhao K">K. Zhao</name></author><author><name sortKey="Chen, Q J" uniqKey="Chen Q">Q.-J. Chen</name></author><author><name sortKey="Deng, F" uniqKey="Deng F">F. Deng</name></author><author><name sortKey="Liu, L L" uniqKey="Liu L">L.-L. Liu</name></author><author><name sortKey="Yan, B" uniqKey="Yan B">B. Yan</name></author><author><name sortKey="Zhan, F X" uniqKey="Zhan F">F.-X. Zhan</name></author><author><name sortKey="Wang, Y Y" uniqKey="Wang Y">Y.-Y. Wang</name></author><author><name sortKey="Xiao, G F" uniqKey="Xiao G">G.-F. Xiao</name></author><author><name sortKey="Shi, Z L" uniqKey="Shi Z">Z.-L. Shi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gallagher, T M" uniqKey="Gallagher T">T. M. Gallagher</name></author><author><name sortKey="Buchmeier, M X0a J" uniqKey="Buchmeier M">M.
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G. Scott</name></author><author><name sortKey="Cowtan, K" uniqKey="Cowtan K">K. Cowtan</name></author></analytic></biblStruct></listBibl></div1></back></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">32132184</article-id><article-id pub-id-type="pmc">7164635</article-id><article-id pub-id-type="publisher-id">abb2762</article-id><article-id pub-id-type="doi">10.1126/science.abb2762</article-id><article-categories><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group><subj-group subj-group-type="legacy-article-type"><subject>R-Articles</subject></subj-group><subj-group subj-group-type="field"><subject>Biochem</subject><subject>Cell Biol</subject></subj-group></article-categories><title-group><article-title>Structural basis for the recognition of SARS-CoV-2 by full-length human
ACE2</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7122-6547</contrib-id><name><surname>Yan</surname><given-names>Renhong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><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/0000-0002-2500-0010</contrib-id><name><surname>Zhang</surname><given-names>Yuanyuan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="author-notes" rid="afn1">*</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yaning</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</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/0000-0003-3007-3086</contrib-id><name><surname>Xia</surname><given-names>Lu</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Yingying</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><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/0000-0002-6237-8813</contrib-id><name><surname>Zhou</surname><given-names>Qiang</given-names></name><xref ref-type="award" rid="award586138"></xref><xref ref-type="award" rid="award594232"></xref><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1">†</xref></contrib><aff id="aff1"><label>1</label>Key Laboratory of Structural Biology of Zhejiang Province, Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</aff><aff id="aff2"><label>2</label>School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China.</aff><aff id="aff3"><label>3</label>Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.</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="zhouqiang@westlake.edu.cn">zhouqiang@westlake.edu.cn</email></corresp></author-notes><pub-date pub-type="ppub"><day>27</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>04</day><month>3</month><year>2020</year></pub-date><volume>367</volume><issue>6485</issue><fpage>1444</fpage><lpage>1448</lpage><history><date date-type="received"><day>12</day><month>2</month><year>2020</year></date><date date-type="accepted"><day>03</day><month>3</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>AAAS</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>How SARS-CoV-2 binds to human cells</title><p>Scientists are racing to learn the secrets of severe acute respiratory
syndrome–coronavirus 2 (SARS-CoV-2), which is the cause of the pandemic disease
COVID-19. The first step in viral entry is the binding of the viral trimeric spike protein
to the human receptor angiotensin-converting enzyme 2 (ACE2). Yan <italic>et al.</italic>present the structure of human ACE2 in complex with a membrane protein that it chaperones,
B<sup>0</sup>AT1. In the context of this complex, ACE2 is a dimer. A further structure
shows how the receptor binding domain of SARS-CoV-2 interacts with ACE2 and suggests that
it is possible that two trimeric spike proteins bind to an ACE2 dimer. The structures
provide a basis for the development of therapeutics targeting this crucial
interaction.</p><p><italic>Science</italic>, this issue p. <ext-link ext-link-type="doi" xlink:href="10.1126/science.abb2762">1444</ext-link></p></abstract><abstract abstract-type="teaser"><p>Insight into how SARS-CoV-2 binds its human receptor could provide a basis for the
development of therapeutics.</p></abstract><abstract><p>Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute
respiratory syndrome–coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2)
that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present
cryo–electron microscopy structures of full-length human ACE2 in the presence of
the neutral amino acid transporter B<sup>0</sup>AT1 with or without the receptor binding
domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an
overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the
ACE2-RBD interface. The ACE2-B<sup>0</sup>AT1 complex is assembled as a dimer of
heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD
is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues.
These findings provide important insights into the molecular basis for coronavirus
recognition and infection.</p></abstract><funding-group><award-group id="award586138"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>31971123</award-id></award-group><award-group id="award586141"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>81920108015</award-id></award-group><award-group id="award586171"><funding-source><institution-wrap><institution-id institution-id-type="doi">http://dx.doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China</institution></institution-wrap></funding-source><award-id>31930059</award-id></award-group><award-group id="award586172"><funding-source><institution-wrap><institution>Key R&D Program of Zhejiang Province</institution></institution-wrap></funding-source><award-id>2020C04001</award-id></award-group><award-group id="award594232"><funding-source><institution-wrap><institution>the SARS-CoV-2 emergency project of the Science and Technology Department
of Zhejiang Province</institution></institution-wrap></funding-source><award-id>2020C03129</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>Number-color-figs</meta-name><meta-value>5</meta-value></custom-meta><custom-meta><meta-name>Number-figs</meta-name><meta-value>5</meta-value></custom-meta><custom-meta><meta-name>Editor</meta-name><meta-value>Valda Vinson</meta-value></custom-meta><custom-meta><meta-name>Copyeditor</meta-name><meta-value>Amelia Beyna</meta-value></custom-meta></custom-meta-group></article-meta></front><body><p>Severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a positive-strand RNA
virus that causes severe respiratory syndrome in humans. The resulting outbreak of coronavirus
disease 2019 (COVID-19) has emerged as a severe epidemic, claiming more than 2000 lives
worldwide between December 2019 and February 2020 (<xref rid="R1" ref-type="bibr"><italic>1</italic></xref>, <xref rid="R2" ref-type="bibr"><italic>2</italic></xref>). The
genome of SARS-CoV-2 shares about 80% identity with that of SARS-CoV and is about 96%
identical to the bat coronavirus BatCoV RaTG13 (<xref rid="R2" ref-type="bibr"><italic>2</italic></xref>).</p><p>In the case of SARS-CoV, the spike glycoprotein (S protein) on the virion surface mediates
receptor recognition and membrane fusion (<xref rid="R3" ref-type="bibr"><italic>3</italic></xref>, <xref rid="R4" ref-type="bibr"><italic>4</italic></xref>).
During viral infection, the trimeric S protein is cleaved into S1 and S2 subunits and S1
subunits are released in the transition to the postfusion conformation (<xref rid="R4" ref-type="bibr"><italic>4</italic></xref>–<xref rid="R7" ref-type="bibr"><italic>7</italic></xref>). S1 contains the receptor binding domain (RBD), which directly
binds to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) (<xref rid="R8" ref-type="bibr"><italic>8</italic></xref>), whereas S2 is responsible for membrane
fusion. When S1 binds to the host receptor ACE2, another cleavage site on S2 is exposed and is
cleaved by host proteases, a process that is critical for viral infection (<xref rid="R5" ref-type="bibr"><italic>5</italic></xref>, <xref rid="R9" ref-type="bibr"><italic>9</italic></xref>, <xref rid="R10" ref-type="bibr"><italic>10</italic></xref>).
The S protein of SARS-CoV-2 may also exploit ACE2 for host infection (<xref rid="R2" ref-type="bibr"><italic>2</italic></xref>, <xref rid="R11" ref-type="bibr"><italic>11</italic></xref>–<xref rid="R13" ref-type="bibr"><italic>13</italic></xref>). A recent publication reported the structure of the S protein
of SARS-CoV-2 and showed that the ectodomain of the SARS-CoV-2 S protein binds to the PD of
ACE2 with a dissociation constant (<italic>K</italic><sub>d</sub>) of ~15 nM (<xref rid="R14" ref-type="bibr"><italic>14</italic></xref>).</p><p>Although ACE2 is hijacked by some coronaviruses, its primary physiological role is in the
maturation of angiotensin (Ang), a peptide hormone that controls vasoconstriction and blood
pressure. ACE2 is a type I membrane protein expressed in lungs, heart, kidneys, and intestine
(<xref rid="R15" ref-type="bibr"><italic>15</italic></xref>–<xref rid="R17" ref-type="bibr"><italic>17</italic></xref>). Decreased expression of ACE2 is associated with
cardiovascular diseases (<xref rid="R18" ref-type="bibr"><italic>18</italic></xref>–<xref rid="R20" ref-type="bibr"><italic>20</italic></xref>). Full-length ACE2 consists of an N-terminal PD and a C-terminal
collectrin-like domain (CLD) that ends with a single transmembrane helix and a ~40-residue
intracellular segment (<xref rid="R15" ref-type="bibr"><italic>15</italic></xref>, <xref rid="R21" ref-type="bibr"><italic>21</italic></xref>). The PD of ACE2 cleaves Ang I to
produce Ang-(1-9), which is then processed by other enzymes to become Ang-(1-7). ACE2 can also
directly process Ang II to give Ang-(1-7) (<xref rid="R15" ref-type="bibr"><italic>15</italic></xref>, <xref rid="R22" ref-type="bibr"><italic>22</italic></xref>).</p><p>Structures of the claw-like ACE2-PD alone and in complex with the RBD or the S protein of
SARS-CoV have revealed the molecular details of the interaction between the RBD of the S
protein and PD of ACE2 (<xref rid="R7" ref-type="bibr"><italic>7</italic></xref>, <xref rid="R8" ref-type="bibr"><italic>8</italic></xref>, <xref rid="R23" ref-type="bibr"><italic>23</italic></xref>, <xref rid="R24" ref-type="bibr"><italic>24</italic></xref>).
Structural information on ACE2 is limited to the PD domain. The single transmembrane (TM)
helix of ACE2 makes it challenging to determine the structure of the full-length protein.</p><p>ACE2 also functions as the chaperone for membrane trafficking of the amino acid transporter
B<sup>0</sup>AT1, also known as SLC6A19 (<xref rid="R25" ref-type="bibr"><italic>25</italic></xref>), which mediates uptake of neutral amino acids into intestinal
cells in a sodium-dependent manner. Mutations in B<sup>0</sup>AT1 may cause Hartnup disorder,
an inherited disease with symptoms such as pellagra, cerebellar ataxia, and psychosis (<xref rid="R26" ref-type="bibr"><italic>26</italic></xref>–<xref rid="R28" ref-type="bibr"><italic>28</italic></xref>). Structures have been determined for the SLC6 family members
<italic>d</italic>DAT (<italic>Drosophila</italic> dopamine transporter) and human SERT
(serotonin transporter, SLC6A4) (<xref rid="R29" ref-type="bibr"><italic>29</italic></xref>,
<xref rid="R30" ref-type="bibr"><italic>30</italic></xref>). It is unclear how ACE2
interacts with B<sup>0</sup>AT1. The membrane trafficking mechanism for ACE2 and
B<sup>0</sup>AT1 is similar to that of the LAT1-4F2hc complex, a large neutral–amino
acid transporter complex that requires 4F2hc for its plasma membrane localization (<xref rid="R31" ref-type="bibr"><italic>31</italic></xref>). Our structure of LAT1-4F2hc shows
that the cargo LAT1 and chaperone 4F2hc interact through both extracellular and transmembrane
domains (<xref rid="R32" ref-type="bibr"><italic>32</italic></xref>). We reasoned that the
structure of full-length ACE2 may be revealed in the presence of B<sup>0</sup>AT1.</p><p>Here, we report cryo–electron microscopy (cryo-EM) structures of the full-length human
ACE2-B<sup>0</sup>AT1 complex at an overall resolution of 2.9 Å and a complex between
the RBD of SARS-CoV-2 and the ACE2-B<sup>0</sup>AT1 complex, also with an overall resolution
of 2.9 Å and with 3.5-Å local resolution at the ACE2-RBD interface. The
ACE2-B<sup>0</sup>AT1 complex exists as a dimer of heterodimers. Structural alignment of the
RBD-ACE2-B<sup>0</sup>AT1 ternary complex with the S protein of SARS-CoV-2 suggests that two
S protein trimers can simultaneously bind to an ACE2 homodimer.</p><sec sec-type="other1" disp-level="1"><title>Structural determination of the ACE2-B<sup>0</sup>AT1 complex</title><p>Full-length human ACE2 and B<sup>0</sup>AT1, with Strep and FLAG tags on their respective N
termini, were coexpressed in human embryonic kidney (HEK) 293F cells and purified through
tandem affinity resin and size exclusion chromatography. The complex was eluted in a single
monodisperse peak, indicating high homogeneity (<xref ref-type="fig" rid="F1">Fig.
1A</xref>). Details of cryo-sample preparation, data acquisition, and structural
determination are given in the materials and methods section of the supplementary materials.
A three-dimensional (3D) reconstruction was obtained at an overall resolution of 2.9
Å from 418,140 selected particles. This immediately revealed the dimer of
heterodimers’ architecture (<xref ref-type="fig" rid="F1">Fig. 1B</xref>). After
applying focused refinement and C2 symmetry expansion, the resolution of the extracellular
domains improved to 2.7 Å, whereas the TM domain remained at 2.9-Å resolution
(<xref ref-type="fig" rid="F1">Fig. 1B</xref>, figs. S1 to S3, and table S1).</p><fig id="F1" fig-type="figure" orientation="portrait" position="float"><label>Fig. 1</label><caption><title>Overall structure of the ACE2-B<sup>0</sup>AT1 complex.</title><p>(<bold>A</bold>) Representative size exclusion chromatography purification profile of
full-length human ACE2 in complex with B<sup>0</sup>AT1. UV, ultraviolet; mAU,
milli–absorbance units; MWM, molecular weight marker. (<bold>B</bold>) Cryo-EM
map of the ACE2-B<sup>0</sup>AT1 complex. The map is generated by merging the focused
refined maps shown in fig. S2. Protomer A of ACE2 (cyan), protomer B of ACE2 (blue),
protomer A of B<sup>0</sup>AT1 (pink) and protomer B of B<sup>0</sup>AT1 (gray) are
shown. (<bold>C</bold>) Cartoon representation of the atomic model of the
ACE2-B<sup>0</sup>AT1 complex. The glycosylation moieties are shown as sticks. The
complex is colored by subunits, with the PD and CLD in one ACE2 protomer colored cyan
and blue, respectively. (<bold>D</bold>) An open conformation of the
ACE2-B<sup>0</sup>AT1 complex. The two PDs, which contact each other in the closed
conformation, are separated in the open conformation.</p></caption><graphic xlink:href="367_1444_F1"></graphic></fig><p>The high resolution supported reliable model building. For ACE2, side chains could be
assigned to residues 19 to 768, which contain the PD (residues 19 to 615) and the CLD
(residues 616 to 768), which consists of a small extracellular domain, a long linker, and
the single TM helix (<xref ref-type="fig" rid="F1">Fig. 1C</xref>). Between the PD and TM
helix is a ferredoxin-like fold domain; we refer to this as the neck domain (residues 616 to
726) (<xref ref-type="fig" rid="F1">Fig. 1C</xref> and fig. S4). Homodimerization is
entirely mediated by ACE2, which is sandwiched by B<sup>0</sup>AT1. Both the PD and neck
domains contribute to dimerization, whereas each B<sup>0</sup>AT1 interacts with the neck
and TM helix in the adjacent ACE2 (<xref ref-type="fig" rid="F1">Fig. 1C</xref>). The
extracellular region is highly glycosylated, with seven and five glycosylation sites on each
ACE2 and B<sup>0</sup>AT1 monomer, respectively.</p><p>During classification, another subset with 143,857 particles was processed to an overall
resolution of 4.5 Å. Whereas the neck domain still dimerizes, the PDs are separated
from each other in this reconstruction (<xref ref-type="fig" rid="F1">Fig. 1D</xref> and
fig. S1, H to K). We therefore define the two classes as the open and closed conformations.
Structural comparison shows that the conformational changes are achieved through rotation of
the PD domains, with the rest of the complex left nearly unchanged (movie S1).</p></sec><sec sec-type="other2" disp-level="1"><title>Homodimer interface of ACE2</title><p>Dimerization of ACE2 is mainly mediated by the neck domain, with the PD contributing a
minor interface (<xref ref-type="fig" rid="F2">Fig. 2A</xref>). The two ACE2 protomers are
hereafter referred to as A and B, with residues in protomer B followed by a prime symbol.
Extensive polar interactions are mapped to the interface between the second (residues 636 to
658) and fourth (residues 708 to 717) helices of the neck domain (<xref ref-type="fig" rid="F2">Fig. 2B</xref>). Arg<sup>652</sup> and Arg<sup>710</sup> in ACE2-A form
cation-π interactions with Tyr<sup>641</sup><sup>′</sup> and
Tyr<sup>633</sup><sup>′</sup> in ACE2-B. Meanwhile, Arg<sup>652</sup> and
Arg<sup>710</sup> are respectively hydrogen-bonded (H-bonded) to
Asn<sup>638</sup><sup>′</sup> and Glu<sup>639</sup><sup>′</sup>, which also
interact with Gln<sup>653</sup>, as does Asn<sup>636</sup><sup>′</sup>.
Ser<sup>709</sup> and Asp<sup>713</sup> from ACE2-A are H-bonded to
Arg<sup>716</sup><sup>′</sup>. This extensive network of polar interactions
indicates stable dimer formation.</p><fig id="F2" fig-type="figure" orientation="portrait" position="float"><label>Fig. 2</label><caption><title>Dimerization interface of ACE2.</title><p>(<bold>A</bold>) ACE2 dimerizes through two interfaces, the PD and the neck domain. The
regions enclosed by the cyan and red dashed lines are illustrated in detail in (B) and
(C), respectively. (<bold>B</bold>) The primary dimeric interface is through the neck
domain in ACE2. Polar interactions are represented by red dashed lines. (<bold>C</bold>)
A weaker interface between PDs of ACE2. The only interaction is between
Gln<sup>139</sup> and Gln<sup>175</sup><sup>′</sup>, which are highlighted as
spheres. The polar residues that may contribute to the stabilization of
Gln<sup>139</sup> are shown as sticks. (<bold>D</bold>) The PDs no longer contact each
other in the open state. Single-letter abbreviations for the amino acid residues used in
the figures are as follows: C, Cys; D, Asp; E, Glu; F, Phe; H, His; K, Lys; L, Leu; M,
Met; N, Asn; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; and Y, Tyr.</p></caption><graphic xlink:href="367_1444_F2"></graphic></fig><p>The PD dimer interface appears much weaker, with only one pair of interactions between
Gln<sup>139</sup> and Gln<sup>175</sup><sup>′</sup> (<xref ref-type="fig" rid="F2">Fig. 2C</xref>). Gln<sup>139</sup> is in a loop that is stabilized by a disulfide bond
between Cys<sup>133</sup> and Cys<sup>141</sup> as well as multiple intraloop polar
interactions (<xref ref-type="fig" rid="F2">Fig. 2C</xref>). The weak interaction is
consistent with the ability to transition to the open conformation, in which the interface
between the neck domains remains the same while the PDs are separated from each other by ~25
Å (<xref ref-type="fig" rid="F2">Fig. 2D</xref> and movie S1).</p></sec><sec sec-type="other3" disp-level="1"><title>Overall structure of the RBD-ACE2-B<sup>0</sup>AT1 complex</title><p>To gain insight into the interaction between ACE2 and SARS-CoV-2, we purchased 0.2 mg of
recombinantly expressed and purified RBD-mFc of SARS-CoV-2 (for simplicity, hereafter
referred to as RBD; mFc, mouse Fc tag) from Sino Biological Inc., mixed it with our purified
ACE2-B<sup>0</sup>AT1 complex at a stoichiometric ratio of ~1.1 to 1, and proceeded with
cryo-grid preparation and imaging. Finally, a 3D EM reconstruction of the ternary complex
was obtained.</p><p>In contrast to the ACE2-B<sup>0</sup>AT1 complex—which has two conformations, open
and closed—only the closed state of ACE2 was observed in the dataset for the
RBD-ACE2-B<sup>0</sup>AT1 ternary complex. The structure of the ternary complex was
determined to an overall resolution of 2.9 Å from 527,017 selected particles.
However, the resolution for the ACE2-B<sup>0</sup>AT1 complex was substantially higher than
that for the RBDs, which are at the periphery of the complex (<xref ref-type="fig" rid="F3">Fig. 3A</xref>). To improve the local resolution, focused refinement was applied; this
allowed us to reach a resolution of 3.5 Å for the RBD, supporting reliable modeling
and analysis of the interface (<xref ref-type="fig" rid="F3">Fig. 3</xref>, figs. S5 to S7,
and table S1).</p><fig id="F3" fig-type="figure" orientation="portrait" position="float"><label>Fig. 3</label><caption><title>Overall structure of the RBD-ACE2-B<sup>0</sup>AT1 complex.</title><p>(<bold>A</bold>) Cryo-EM map of the RBD-ACE2-B<sup>0</sup>AT1 complex. The overall
reconstruction of the ternary complex at 2.9 Å is shown on the left. The inset
shows the focused refined map of RBD. The color scheme is the same as that in <xref ref-type="fig" rid="F1">Fig. 1B</xref>, with the addition of red and gold, which
represent RBD protomers. (<bold>B</bold>) Overall structure of the
RBD-ACE2-B<sup>0</sup>AT1 complex. The color scheme is the same as that in <xref ref-type="fig" rid="F1">Fig. 1C</xref>. The glycosylation moieties are shown as
sticks.</p></caption><graphic xlink:href="367_1444_F3"></graphic></fig></sec><sec sec-type="other4" disp-level="1"><title>Interface between the RBD and ACE2</title><p>As expected, each PD accommodates one RBD (<xref ref-type="fig" rid="F3">Fig. 3B</xref>).
The overall interface is similar to that between SARS-CoV and ACE2 (<xref rid="R7" ref-type="bibr"><italic>7</italic></xref>, <xref rid="R8" ref-type="bibr"><italic>8</italic></xref>), mediated mainly through polar interactions (<xref ref-type="fig" rid="F4">Fig. 4A</xref>). An extended loop region of the RBD spans the
arch-shaped α1 helix of the ACE2-PD like a bridge. The α2 helix and a loop
that connects the β3 and β4 antiparallel strands, referred to as loop 3-4, of
the PD also make limited contributions to the coordination of the RBD.</p><fig id="F4" fig-type="figure" orientation="portrait" position="float"><label>Fig. 4</label><caption><title>Interactions between SARS-CoV-2-RBD and ACE2.</title><p>(<bold>A</bold>) The PD of ACE2 mainly engages the α1 helix in the recognition
of the RBD. The α2 helix and the linker between β3 and β4 also
contribute to the interaction. Only one RBD-ACE2 is shown. (<bold>B</bold> to
<bold>D</bold>) Detailed analysis of the interface between SARS-CoV-2-RBD and ACE2.
Polar interactions are indicated by red dashed lines. NAG,
<italic>N</italic>-acetylglucosamine.</p></caption><graphic xlink:href="367_1444_F4"></graphic></fig><p>The contact can be divided into three clusters. The two ends of the bridge interact with
the N and C termini of the α1 helix as well as small areas on the α2 helix and
loop 3-4. The middle segment of α1 reinforces the interaction by engaging two polar
residues (<xref ref-type="fig" rid="F4">Fig. 4A</xref>). At the N terminus of α1,
Gln<sup>498</sup>, Thr<sup>500</sup>, and Asn<sup>501</sup> of the RBD form a network of
H-bonds with Tyr<sup>41</sup>, Gln<sup>42</sup>, Lys<sup>353</sup>, and Arg<sup>357</sup>from ACE2 (<xref ref-type="fig" rid="F4">Fig. 4B</xref>). In the middle of the bridge,
Lys<sup>417</sup> and Tyr<sup>453</sup> of the RBD interact with Asp<sup>30</sup> and
His<sup>34</sup> of ACE2, respectively (<xref ref-type="fig" rid="F4">Fig. 4C</xref>). At
the C terminus of α1, Gln<sup>474</sup> of the RBD is H-bonded to Gln<sup>24</sup> of
ACE2, whereas Phe<sup>486</sup> of the RBD interacts with Met<sup>82</sup> of ACE2 through
van der Waals forces (<xref ref-type="fig" rid="F4">Fig. 4D</xref>).</p></sec><sec sec-type="other5" disp-level="1"><title>Comparing the SARS-CoV-2 and SARS-CoV interfaces with ACE2</title><p>Superimposition of the RBD in the complex of SARS-CoV (SARS-CoV-RBD) and ACE2-PD [Protein
Data Bank (PDB) 2AJF] with the RBD in our ternary complex shows that the SARS-CoV-2 RBD
(SARS-CoV-2-RBD) is similar to SARS-CoV-RBD with a root mean square deviation (RMSD) of 0.68
Å over 139 pairs of Cα atoms (<xref ref-type="fig" rid="F5">Fig. 5A</xref>)
(<xref rid="R8" ref-type="bibr"><italic>8</italic></xref>). Despite the overall
similarity, a number of sequence variations and conformational deviations are found in their
respective interfaces with ACE2 (<xref ref-type="fig" rid="F5">Fig. 5</xref> and fig. S8).
At the N terminus of α1, the variations Arg<sup>426</sup>→Asn<sup>439</sup>,
Tyr<sup>484</sup>→Gln<sup>498</sup>, and Thr<sup>487</sup>→Asn<sup>501</sup>at equivalent positions are observed between SARS-CoV-RBD and SARS-CoV-2-RBD (<xref ref-type="fig" rid="F5">Fig. 5B</xref>). More variations are observed in the middle of the
bridge. The most prominent alteration is the substitution of Val<sup>404</sup> in the
SARS-CoV-RBD with Lys<sup>417</sup> in the SARS-CoV-2-RBD. In addition, from SARS-CoV-RBD to
SARS-CoV-2-RBD, the substitution of interface residues
Tyr<sup>442</sup>→Leu<sup>455</sup>, Leu<sup>443</sup>→Phe<sup>456</sup>,
Phe<sup>460</sup>→Tyr<sup>473</sup>, and Asn<sup>479</sup>→Gln<sup>493</sup>may also change the affinity for ACE2 (<xref ref-type="fig" rid="F5">Fig. 5C</xref>). At the
C terminus of α1, Leu<sup>472</sup> in the SARS-CoV-RBD is replaced by
Phe<sup>486</sup> in the SARS-CoV-2-RBD (<xref ref-type="fig" rid="F5">Fig.
5D</xref>).</p><fig id="F5" fig-type="figure" orientation="portrait" position="float"><label>Fig. 5</label><caption><title>Interface comparison between SARS-CoV-2-RBD and SARS-CoV-RBD with ACE2.</title><p>(<bold>A</bold>) Structural alignment for the SARS-CoV-2-RBD and SARS-CoV-RBD. The
structure of the ACE2-PD and the SARS-CoV-RBD complex (PDB 2AJF) is superimposed on our
cryo-EM structure of the ternary complex relative to the RBDs. The regions enclosed by
the purple, blue, and red dashed lines are illustrated in detail in (B) to (D),
respectively. SARS-CoV-2-RBD and the PD in our cryo-EM structure are colored orange and
cyan, respectively; SARS-CoV-RBD and its complexed PD are colored green and gold,
respectively. (<bold>B</bold> to <bold>D</bold>) Variation of the interface residues
between SARS-CoV-2-RBD (labeled in brown) and SARS-CoV-RBD (labeled in green).</p></caption><graphic xlink:href="367_1444_F5"></graphic></fig></sec><sec sec-type="discussion" disp-level="1"><title>Discussion</title><p>Although ACE2 is a chaperone for B<sup>0</sup>AT1, our focus is on ACE2 in this study. With
the stabilization by B<sup>0</sup>AT1, we elucidated the structure of full-length ACE2.
B<sup>0</sup>AT1 is not involved in dimerization, suggesting that ACE2 may be a homodimer
even in the absence of B<sup>0</sup>AT1. Further examination suggests that a dimeric ACE2
can accommodate two S protein trimers, each through a monomer of ACE2 (fig. S9). The
trimeric structure of the S protein of SARS-CoV-2 was recently reported, with one RBD in an
up conformation and two in down conformations (PDB 6VSB) (<xref rid="R14" ref-type="bibr"><italic>14</italic></xref>). The PD clashes with the rest of the S protein when the
ternary complex is aligned to the RBD of the down conformation. There is no clash when the
complex is superimposed on RDB in the up conformation, with a RMSD of 0.98 Å over 126
pairs of C<sub>α</sub> atoms, confirming that an up conformation of RDB is required
to bind to the receptor (fig. S9) (<xref rid="R14" ref-type="bibr"><italic>14</italic></xref>).</p><p>Cleavage of the S protein of SARS-CoV is facilitated by cathepsin L in endosomes,
indicating a mechanism of receptor-mediated endocytosis (<xref rid="R10" ref-type="bibr"><italic>10</italic></xref>). Further characterization is required to examine the
interactions between ACE2 and the viral particle as well as the effect of cofactors on this
process (<xref rid="R25" ref-type="bibr"><italic>25</italic></xref>, <xref rid="R33" ref-type="bibr"><italic>33</italic></xref>). It remains to be investigated whether there is
clustering between the dimeric ACE2 and trimeric S proteins, which may be important for
invagination of the membrane and endocytosis of the viral particle, a process similar to
other types of receptor-mediated endocytosis.</p><p>Cleavage of the C-terminal segment, especially residues 697 to 716 (fig. S4), of ACE2 by
proteases, such as transmembrane protease serine 2 (TMPRSS2), enhances the S
protein–driven viral entry (<xref rid="R34" ref-type="bibr"><italic>34</italic></xref>, <xref rid="R35" ref-type="bibr"><italic>35</italic></xref>).
Residues 697 to 716 form the third and fourth helices in the neck domain and map to the
dimeric interface of ACE2. The presence of B<sup>0</sup>AT1 may block the access of TMPRSS2
to the cutting site on ACE2. The expression distribution of ACE2 is broader than that of
B<sup>0</sup>AT1. In addition to kidneys and intestine, where B<sup>0</sup>AT1 is mainly
expressed, ACE2 is also expressed in lungs and heart (<xref rid="R27" ref-type="bibr"><italic>27</italic></xref>). It remains to be tested whether B<sup>0</sup>AT1 can
suppress SARS-CoV-2 infection by blocking ACE2 cleavage. Enteric infections have been
reported for SARS-CoV, and possibly also for SARS-CoV-2 (<xref rid="R36" ref-type="bibr"><italic>36</italic></xref>, <xref rid="R37" ref-type="bibr"><italic>37</italic></xref>). B<sup>0</sup>AT1 has also been shown to interact with another
coronavirus receptor, aminopeptidase N (APN or CD13) (<xref rid="R38" ref-type="bibr"><italic>38</italic></xref>). These findings suggest that B<sup>0</sup>AT1 may play a
regulatory role for the enteric infections of some coronaviruses.</p><p>Comparing the interaction interfaces of SARS-CoV-2-RBD and SARS-CoV-RBD with ACE2 reveals
some variations that may strengthen the interactions between SARS-CoV-2-RBD and ACE2 and
other variations that are likely to reduce the affinity compared with SARS-CoV-RBD and ACE2.
For instance, the change from Val<sup>404</sup> to Lys<sup>317</sup> may result in a tighter
association because of the salt bridge formation between Lys<sup>317</sup> and
Asp<sup>30</sup> of ACE2 (<xref ref-type="fig" rid="F4">Figs. 4C</xref> and <xref ref-type="fig" rid="F5">5C</xref>). The change from Leu<sup>472</sup> to Phe<sup>486</sup>may also result in a stronger van der Waals contact with Met<sup>82</sup> (<xref ref-type="fig" rid="F5">Fig. 5D</xref>). However, replacement of Arg<sup>426</sup> with
Asn<sup>439</sup> appears to weaken the interaction by eliminating one important salt
bridge with Asp<sup>329</sup> on ACE2 (<xref ref-type="fig" rid="F5">Fig. 5B</xref>).</p><p>Our structural work reveals the high-resolution structure of full-length ACE2 in a dimeric
assembly. Docking the S protein trimer onto the structure of the ACE2 dimer with the RBD of
the S protein bound suggests simultaneous binding of two S protein trimers to an ACE2 dimer.
Structure-based rational design of binders with enhanced affinities to either ACE2 or the S
protein of the coronaviruses may facilitate development of decoy ligands or neutralizing
antibodies for suppression of viral infection.</p></sec></body><back><ack><title>Acknowledgments</title><p>We thank the Cryo-EM Facility and Supercomputer Center of Westlake University for providing
cryo-EM and computation support, respectively. This work was funded by the National Natural
Science Foundation of China (projects 31971123, 81920108015, and 31930059), the
Key R&D Program of Zhejiang Province (2020C04001), and the SARS-CoV-2
emergency project of the Science and Technology Department of Zhejiang Province
(2020C03129). <bold>Author contributions:</bold> Q.Z. and R.Y. conceived the project. Q.Z.
and R.Y. designed the experiments. All authors performed the experiments. Q.Z., R.Y., Y.Z.,
and Y.L. contributed to data analysis. Q.Z. and R.Y. wrote the manuscript. <bold>Competing
interests:</bold> The authors declare no competing interests. <bold>Data and materials
availability:</bold> Atomic coordinates and cryo EM maps for the ACE2-B<sup>0</sup>AT1
complex of closed conformation (whole structure and map, PDB 6M18 and EMD-30040;
extracellular region map, EMD-30044; and TM region map, EMD-30045), the
ACE2-B<sup>0</sup>AT1 complex of open conformation (PDB 6M1D and EMD-30041), and the complex
of the RBD of SARS-CoV-2 with the ACE2-B<sup>0</sup>AT1 complex (whole structure and map,
PDB 6M17 and EMD-30039; extracellular region map, EMD-30042; TM region map, EMD-30043; and
ACE2-RBD interface map, EMD-30046) have been deposited in the Protein Data Bank (<ext-link ext-link-type="uri" xlink:href="http://www.rcsb.org/">www.rcsb.org</ext-link>) and the
Electron Microscopy Data Bank (<ext-link ext-link-type="uri" xlink:href="https://www.ebi.ac.uk/pdbe/emdb/">www.ebi.ac.uk/pdbe/emdb/</ext-link>).
Correspondence and requests for materials should be addressed to corresponding author Q.Z.
This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0)
license, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited. To view a copy of this license, visit
<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</ext-link>. This license does not apply to
figures/photos/artwork or other content included in the article that is credited to a third
party; obtain authorization from the rights holder before using such material.</p></ack><app-group><app><title>Supplementary Materials</title><supplementary-material content-type="local-data"><p><ext-link ext-link-type="uri" xlink:href="http://science.sciencemag.org/content/367/6485/1444/suppl/DC1">science.sciencemag.org/content/367/6485/1444/suppl/DC1</ext-link></p><p>Materials and Methods</p><p>Figs. S1 to S9</p><p>Table S1</p><p>References (<xref rid="R39" ref-type="bibr"><italic>39</italic></xref>–<xref rid="R52" ref-type="bibr"><italic>52</italic></xref>)</p><p>MDAR Reproducibility Checklist</p><p>Movie S1</p></supplementary-material><supplementary-material content-type="local-data" id="S1"><media xlink:href="abb2762_MDAR_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="abb2762_Yan_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="abb2762s1.mp4"><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.abb2762">View/request a protocol for this paper from
<italic>Bio-protocol</italic></ext-link>.</p></app></app-group><ref-list><title>References and notes</title><ref id="R1"><label>1</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Zhu</surname><given-names>N.</given-names></name>, <name name-style="western"><surname>Zhang</surname><given-names>D.</given-names></name>, <name name-style="western"><surname>Wang</surname><given-names>W.</given-names></name>, <name name-style="western"><surname>Li</surname><given-names>X.</given-names></name>, <name name-style="western"><surname>Yang</surname><given-names>B.</given-names></name>, <name name-style="western"><surname>Song</surname><given-names>J.</given-names></name>, <name name-style="western"><surname>Zhao</surname><given-names>X.</given-names></name>, <name name-style="western"><surname>Huang</surname><given-names>B.</given-names></name>, <name name-style="western"><surname>Shi</surname><given-names>W.</given-names></name>, <name name-style="western"><surname>Lu</surname><given-names>R.</given-names></name>, <name name-style="western"><surname>Niu</surname><given-names>P.</given-names></name>, <name name-style="western"><surname>Zhan</surname><given-names>F.</given-names></name>, <name name-style="western"><surname>Ma</surname><given-names>X.</given-names></name>, <name name-style="western"><surname>Wang</surname><given-names>D.</given-names></name>, <name name-style="western"><surname>Xu</surname><given-names>W.</given-names></name>, <name name-style="western"><surname>Wu</surname><given-names>G.</given-names></name>, <name name-style="western"><surname>Gao</surname><given-names>G. F.</given-names></name>, <name name-style="western"><surname>Tan</surname><given-names>W.</given-names></name>; <collab>China Novel Coronavirus Investigating
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<pub-id pub-id-type="doi">10.1107/S0907444910007493</pub-id><pub-id pub-id-type="pmid">20383002</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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