Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles
The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron...
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| Veröffentlicht in: | Nature structural & molecular biology 2020-08, Vol.27 (8), p.726-734 |
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| creator | Li, Ze Li, Wenwei Lu, Maolin Bess, Julian Chao, Cara W. Gorman, Jason Terry, Daniel S. Zhang, Baoshan Zhou, Tongqing Blanchard, Scott C. Kwong, Peter D. Lifson, Jeffrey D. Mothes, Walther Liu, Jun |
| description | The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron tomography and subtomogram averaging to determine the structures of Env trimers on aldrithiol-2 (AT-2)-inactivated virions in ligand-free, antibody-bound and CD4-bound forms at subnanometer resolution. Tomographic reconstructions document molecular features consistent with high-resolution structures of engineered soluble and detergent-solubilized Env trimers. One of three conformational states previously predicted by smFRET was not observed by cryo-ET, potentially owing to AT-2 inactivation. We did observe Env trimers to open in situ in response to CD4 binding, with an outward movement of gp120-variable loops and an extension of a critical gp41 helix. Overall features of Env trimer embedded in AT-2-treated virions appear well-represented by current engineered trimers.
Cryo-ET and subtomogram averaging analyses are used to determine structures of HIV-1 Env trimers on the surface of inactivated virions. |
| doi_str_mv | 10.1038/s41594-020-0452-2 |
| format | Article |
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Cryo-ET and subtomogram averaging analyses are used to determine structures of HIV-1 Env trimers on the surface of inactivated virions.</description><identifier>ISSN: 1545-9993</identifier><identifier>ISSN: 1545-9985</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-020-0452-2</identifier><identifier>PMID: 32601441</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>101/28 ; 14/33 ; 2,2'-Dipyridyl - analogs & derivatives ; 2,2'-Dipyridyl - pharmacology ; 631/535/1258/1260 ; 631/57/2271 ; Antibodies ; Binding sites ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Cancer ; CD4 antigen ; Cell Line ; Cryoelectron Microscopy ; Deactivation ; Disulfides - pharmacology ; Electron Microscope Tomography ; Glycoprotein gp120 ; Glycoprotein gp41 ; Glycoproteins ; HIV ; HIV Envelope Protein gp120 - chemistry ; HIV Envelope Protein gp120 - ultrastructure ; HIV Envelope Protein gp41 - chemistry ; HIV Envelope Protein gp41 - ultrastructure ; HIV Infections - virology ; HIV-1 - chemistry ; HIV-1 - drug effects ; Human immunodeficiency virus ; Humans ; Inactivation ; Life Sciences ; Ligands ; Medical research ; Membrane Biology ; Models, Molecular ; Molecular biology ; Oxidants - pharmacology ; Protein Conformation - drug effects ; Protein Multimerization - drug effects ; Protein Structure ; Solubility ; Trimers ; Virion - chemistry ; Virion - drug effects ; Virions ; Viruses</subject><ispartof>Nature structural & molecular biology, 2020-08, Vol.27 (8), p.726-734</ispartof><rights>This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020</rights><rights>This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-f5ea734622e170a46dbd8e2721e86476fd8c56777f08b6f35150d14004f307493</citedby><cites>FETCH-LOGICAL-c415t-f5ea734622e170a46dbd8e2721e86476fd8c56777f08b6f35150d14004f307493</cites><orcidid>0000-0003-2717-9365 ; 0000-0002-3367-7240 ; 0000-0003-3008-6901 ; 0000-0003-3108-6735</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41594-020-0452-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41594-020-0452-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32601441$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Ze</creatorcontrib><creatorcontrib>Li, Wenwei</creatorcontrib><creatorcontrib>Lu, Maolin</creatorcontrib><creatorcontrib>Bess, Julian</creatorcontrib><creatorcontrib>Chao, Cara W.</creatorcontrib><creatorcontrib>Gorman, Jason</creatorcontrib><creatorcontrib>Terry, Daniel S.</creatorcontrib><creatorcontrib>Zhang, Baoshan</creatorcontrib><creatorcontrib>Zhou, Tongqing</creatorcontrib><creatorcontrib>Blanchard, Scott C.</creatorcontrib><creatorcontrib>Kwong, Peter D.</creatorcontrib><creatorcontrib>Lifson, Jeffrey D.</creatorcontrib><creatorcontrib>Mothes, Walther</creatorcontrib><creatorcontrib>Liu, Jun</creatorcontrib><title>Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron tomography and subtomogram averaging to determine the structures of Env trimers on aldrithiol-2 (AT-2)-inactivated virions in ligand-free, antibody-bound and CD4-bound forms at subnanometer resolution. Tomographic reconstructions document molecular features consistent with high-resolution structures of engineered soluble and detergent-solubilized Env trimers. One of three conformational states previously predicted by smFRET was not observed by cryo-ET, potentially owing to AT-2 inactivation. We did observe Env trimers to open in situ in response to CD4 binding, with an outward movement of gp120-variable loops and an extension of a critical gp41 helix. Overall features of Env trimer embedded in AT-2-treated virions appear well-represented by current engineered trimers.
Cryo-ET and subtomogram averaging analyses are used to determine structures of HIV-1 Env trimers on the surface of inactivated virions.</description><subject>101/28</subject><subject>14/33</subject><subject>2,2'-Dipyridyl - analogs & derivatives</subject><subject>2,2'-Dipyridyl - pharmacology</subject><subject>631/535/1258/1260</subject><subject>631/57/2271</subject><subject>Antibodies</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer</subject><subject>CD4 antigen</subject><subject>Cell Line</subject><subject>Cryoelectron Microscopy</subject><subject>Deactivation</subject><subject>Disulfides - pharmacology</subject><subject>Electron Microscope Tomography</subject><subject>Glycoprotein gp120</subject><subject>Glycoprotein gp41</subject><subject>Glycoproteins</subject><subject>HIV</subject><subject>HIV Envelope Protein gp120 - chemistry</subject><subject>HIV Envelope Protein gp120 - ultrastructure</subject><subject>HIV Envelope Protein gp41 - chemistry</subject><subject>HIV Envelope Protein gp41 - ultrastructure</subject><subject>HIV Infections - virology</subject><subject>HIV-1 - chemistry</subject><subject>HIV-1 - drug effects</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Medical research</subject><subject>Membrane Biology</subject><subject>Models, Molecular</subject><subject>Molecular biology</subject><subject>Oxidants - pharmacology</subject><subject>Protein Conformation - drug effects</subject><subject>Protein Multimerization - drug effects</subject><subject>Protein Structure</subject><subject>Solubility</subject><subject>Trimers</subject><subject>Virion - chemistry</subject><subject>Virion - drug effects</subject><subject>Virions</subject><subject>Viruses</subject><issn>1545-9993</issn><issn>1545-9985</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kE1LAzEQhoMotlZ_gBdZ8OIlOvna7B6lqC0UPPhxk5DuzuqW7W5NsgX_vSmtFQRPE5hn3sk8hJwzuGYgshsvmcolBQ4UpOKUH5AhU1LRPM_U4f6diwE58X4BwJXS4pgMBE-BScmG5O2pn7e27ZYY0CU-uL4IvUOfdFUymb5SlmC7xqZbYRJcvUQXO21im9LV4aPuGspp3doi1GsbsEzWtet9srIu1EWD_pQcVbbxeLarI_Jyf_c8ntDZ48N0fDujRbwg0Eqh1UKmnCPTYGVazssMueYMs1TqtCqzQqVa6wqyeVoJxRSUTALISoCWuRiRq23uynWfPfpglrUvsGlsi13vDZcsh0ymWkT08g-66HrXxt9FSkDGtMhVpNiWKlznvcPKrOL11n0ZBmbj3mzdm-jebNwbHmcudsn9fInlfuJHdgT4FvCx1b6j-139f-o3mV2Npw</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Li, Ze</creator><creator>Li, Wenwei</creator><creator>Lu, Maolin</creator><creator>Bess, Julian</creator><creator>Chao, Cara W.</creator><creator>Gorman, Jason</creator><creator>Terry, Daniel S.</creator><creator>Zhang, Baoshan</creator><creator>Zhou, Tongqing</creator><creator>Blanchard, Scott C.</creator><creator>Kwong, Peter D.</creator><creator>Lifson, Jeffrey D.</creator><creator>Mothes, Walther</creator><creator>Liu, Jun</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PADUT</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2717-9365</orcidid><orcidid>https://orcid.org/0000-0002-3367-7240</orcidid><orcidid>https://orcid.org/0000-0003-3008-6901</orcidid><orcidid>https://orcid.org/0000-0003-3108-6735</orcidid></search><sort><creationdate>20200801</creationdate><title>Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles</title><author>Li, Ze ; Li, Wenwei ; Lu, Maolin ; Bess, Julian ; Chao, Cara W. ; Gorman, Jason ; Terry, Daniel S. ; Zhang, Baoshan ; Zhou, Tongqing ; Blanchard, Scott C. ; Kwong, Peter D. ; Lifson, Jeffrey D. ; Mothes, Walther ; Liu, Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-f5ea734622e170a46dbd8e2721e86476fd8c56777f08b6f35150d14004f307493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>101/28</topic><topic>14/33</topic><topic>2,2'-Dipyridyl - analogs & derivatives</topic><topic>2,2'-Dipyridyl - pharmacology</topic><topic>631/535/1258/1260</topic><topic>631/57/2271</topic><topic>Antibodies</topic><topic>Binding sites</topic><topic>Biochemistry</topic><topic>Biological Microscopy</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer</topic><topic>CD4 antigen</topic><topic>Cell Line</topic><topic>Cryoelectron Microscopy</topic><topic>Deactivation</topic><topic>Disulfides - pharmacology</topic><topic>Electron Microscope Tomography</topic><topic>Glycoprotein gp120</topic><topic>Glycoprotein gp41</topic><topic>Glycoproteins</topic><topic>HIV</topic><topic>HIV Envelope Protein gp120 - chemistry</topic><topic>HIV Envelope Protein gp120 - ultrastructure</topic><topic>HIV Envelope Protein gp41 - chemistry</topic><topic>HIV Envelope Protein gp41 - ultrastructure</topic><topic>HIV Infections - virology</topic><topic>HIV-1 - chemistry</topic><topic>HIV-1 - drug effects</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Life Sciences</topic><topic>Ligands</topic><topic>Medical research</topic><topic>Membrane Biology</topic><topic>Models, Molecular</topic><topic>Molecular biology</topic><topic>Oxidants - 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Academic</collection><jtitle>Nature structural & molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Ze</au><au>Li, Wenwei</au><au>Lu, Maolin</au><au>Bess, Julian</au><au>Chao, Cara W.</au><au>Gorman, Jason</au><au>Terry, Daniel S.</au><au>Zhang, Baoshan</au><au>Zhou, Tongqing</au><au>Blanchard, Scott C.</au><au>Kwong, Peter D.</au><au>Lifson, Jeffrey D.</au><au>Mothes, Walther</au><au>Liu, Jun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles</atitle><jtitle>Nature structural & molecular biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Mol Biol</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>27</volume><issue>8</issue><spage>726</spage><epage>734</epage><pages>726-734</pages><issn>1545-9993</issn><issn>1545-9985</issn><eissn>1545-9985</eissn><abstract>The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron tomography and subtomogram averaging to determine the structures of Env trimers on aldrithiol-2 (AT-2)-inactivated virions in ligand-free, antibody-bound and CD4-bound forms at subnanometer resolution. Tomographic reconstructions document molecular features consistent with high-resolution structures of engineered soluble and detergent-solubilized Env trimers. One of three conformational states previously predicted by smFRET was not observed by cryo-ET, potentially owing to AT-2 inactivation. We did observe Env trimers to open in situ in response to CD4 binding, with an outward movement of gp120-variable loops and an extension of a critical gp41 helix. Overall features of Env trimer embedded in AT-2-treated virions appear well-represented by current engineered trimers.
Cryo-ET and subtomogram averaging analyses are used to determine structures of HIV-1 Env trimers on the surface of inactivated virions.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32601441</pmid><doi>10.1038/s41594-020-0452-2</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-2717-9365</orcidid><orcidid>https://orcid.org/0000-0002-3367-7240</orcidid><orcidid>https://orcid.org/0000-0003-3008-6901</orcidid><orcidid>https://orcid.org/0000-0003-3108-6735</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 101/28 14/33 2,2'-Dipyridyl - analogs & derivatives 2,2'-Dipyridyl - pharmacology 631/535/1258/1260 631/57/2271 Antibodies Binding sites Biochemistry Biological Microscopy Biomedical and Life Sciences Cancer CD4 antigen Cell Line Cryoelectron Microscopy Deactivation Disulfides - pharmacology Electron Microscope Tomography Glycoprotein gp120 Glycoprotein gp41 Glycoproteins HIV HIV Envelope Protein gp120 - chemistry HIV Envelope Protein gp120 - ultrastructure HIV Envelope Protein gp41 - chemistry HIV Envelope Protein gp41 - ultrastructure HIV Infections - virology HIV-1 - chemistry HIV-1 - drug effects Human immunodeficiency virus Humans Inactivation Life Sciences Ligands Medical research Membrane Biology Models, Molecular Molecular biology Oxidants - pharmacology Protein Conformation - drug effects Protein Multimerization - drug effects Protein Structure Solubility Trimers Virion - chemistry Virion - drug effects Virions Viruses |
| title | Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles |
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