Structural basis of coreceptor recognition by HIV-1 envelope spike
HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160) 3 cleaved to (gp120 and gp41) 3 , interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as...
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| Veröffentlicht in: | Nature (London) 2019-01, Vol.565 (7739), p.318-323 |
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| creator | Shaik, Md Munan Peng, Hanqin Lu, Jianming Rits-Volloch, Sophia Xu, Chen Liao, Maofu Chen, Bing |
| description | HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160)
3
cleaved to (gp120 and gp41)
3
, interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and the N terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry into host cells and may guide the development of vaccines and therapeutic agents.
The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1. |
| doi_str_mv | 10.1038/s41586-018-0804-9 |
| format | Article |
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3
cleaved to (gp120 and gp41)
3
, interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and the N terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry into host cells and may guide the development of vaccines and therapeutic agents.
The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-018-0804-9</identifier><identifier>PMID: 30542158</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/28 ; 631/535 ; 631/535/1258/1259 ; 82/83 ; Allosteric properties ; Analysis ; Anchoring ; Anti-HIV Agents - chemistry ; Anti-HIV Agents - metabolism ; Automation ; Binding Sites ; CCR5 protein ; CD4 antigen ; CD4 Antigens - chemistry ; CD4 Antigens - isolation & purification ; CD4 Antigens - metabolism ; CD4 Antigens - ultrastructure ; Cell Line ; Cell membranes ; Chemical compounds ; Chemokine CCL5 - chemistry ; Chemokine CCL5 - metabolism ; Chemokines ; Conformation ; Cryoelectron microscopy ; Electron microscopy ; Genetic aspects ; Glycoprotein gp120 ; Glycoprotein gp160 ; Glycoprotein gp41 ; Glycoproteins ; Helices ; HIV ; HIV Envelope Protein gp120 - chemistry ; HIV Envelope Protein gp120 - isolation & purification ; HIV Envelope Protein gp120 - metabolism ; HIV Envelope Protein gp120 - ultrastructure ; HIV Envelope Protein gp41 - chemistry ; HIV Envelope Protein gp41 - metabolism ; HIV Envelope Protein gp41 - ultrastructure ; Human immunodeficiency virus ; Humanities and Social Sciences ; Humans ; Inserts ; Ligands ; Maraviroc - chemistry ; Maraviroc - metabolism ; Membranes ; Microscopy ; Models, Molecular ; multidisciplinary ; Pharmacology ; Protein Binding ; Protein Conformation ; Protein structure ; Proteins ; Receptors, CCR5 - chemistry ; Receptors, CCR5 - isolation & purification ; Receptors, CCR5 - metabolism ; Receptors, CCR5 - ultrastructure ; Receptors, HIV - antagonists & inhibitors ; Receptors, HIV - chemistry ; Receptors, HIV - metabolism ; Receptors, HIV - ultrastructure ; Science ; Science (multidisciplinary) ; Signal transduction ; Structure ; Trimers ; Vaccines ; Viruses</subject><ispartof>Nature (London), 2019-01, Vol.565 (7739), p.318-323</ispartof><rights>Springer Nature Limited 2018</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 17, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c738t-7e335e86941ae42c842fbfb4fca00d731e2302cb02ef27c3086c7c337b0570863</citedby><cites>FETCH-LOGICAL-c738t-7e335e86941ae42c842fbfb4fca00d731e2302cb02ef27c3086c7c337b0570863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-018-0804-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-018-0804-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30542158$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shaik, Md Munan</creatorcontrib><creatorcontrib>Peng, Hanqin</creatorcontrib><creatorcontrib>Lu, Jianming</creatorcontrib><creatorcontrib>Rits-Volloch, Sophia</creatorcontrib><creatorcontrib>Xu, Chen</creatorcontrib><creatorcontrib>Liao, Maofu</creatorcontrib><creatorcontrib>Chen, Bing</creatorcontrib><title>Structural basis of coreceptor recognition by HIV-1 envelope spike</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160)
3
cleaved to (gp120 and gp41)
3
, interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and the N terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry into host cells and may guide the development of vaccines and therapeutic agents.
The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1.</description><subject>101/28</subject><subject>631/535</subject><subject>631/535/1258/1259</subject><subject>82/83</subject><subject>Allosteric properties</subject><subject>Analysis</subject><subject>Anchoring</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Anti-HIV Agents - metabolism</subject><subject>Automation</subject><subject>Binding Sites</subject><subject>CCR5 protein</subject><subject>CD4 antigen</subject><subject>CD4 Antigens - chemistry</subject><subject>CD4 Antigens - isolation & purification</subject><subject>CD4 Antigens - metabolism</subject><subject>CD4 Antigens - ultrastructure</subject><subject>Cell Line</subject><subject>Cell membranes</subject><subject>Chemical compounds</subject><subject>Chemokine CCL5 - chemistry</subject><subject>Chemokine CCL5 - 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chemistry</subject><subject>Maraviroc - metabolism</subject><subject>Membranes</subject><subject>Microscopy</subject><subject>Models, Molecular</subject><subject>multidisciplinary</subject><subject>Pharmacology</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Receptors, CCR5 - chemistry</subject><subject>Receptors, CCR5 - isolation & purification</subject><subject>Receptors, CCR5 - metabolism</subject><subject>Receptors, CCR5 - ultrastructure</subject><subject>Receptors, HIV - antagonists & inhibitors</subject><subject>Receptors, HIV - chemistry</subject><subject>Receptors, HIV - metabolism</subject><subject>Receptors, HIV - ultrastructure</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>Structure</subject><subject>Trimers</subject><subject>Vaccines</subject><subject>Viruses</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kk1v1DAQhi0EotuFH8AFRXABoRR_JXYuSMsK6EoVSLTA0XK8k-CStVM7qdp_j1db2gZt5cPYnmdef8yL0AuCjwhm8n3kpJBljonMscQ8rx6hGeGizHkpxWM0w5huM6w8QIcxnmOMCyL4U3TAcMFpqp2hj6dDGM0wBt1ltY42Zr7JjA9goB98yNLEt84O1rusvs6OVz9zkoG7hM73kMXe_oFn6EmjuwjPb-Ic_fj86Wx5nJ98-7JaLk5yI5gccgGMFSDLihMNnBrJaVM3NW-MxngtGAHKMDU1ptBQYRiWpUmBiRoXIi3YHH3Y6fZjvYG1ATekW6s-2I0O18prq6YZZ3-r1l-qklVECpEE3twIBH8xQhzUxkYDXacd-DGq9CNFRZiQRUJf_4ee-zG49LxECVKSoirZHdXqDpR1jU_nmq2oWhSCUcFx0pujfA_VgoN0Se-gsWl7wr_aw5veXqj70NEeKI01bKzZq_p2UpCYAa6GVo8xqtXp9yn77mF2cfZr-XVKkx1tgo8xQHPbEoLV1qdq51OVfKq2PlVVqnl5v5e3Ff-MmQC6A2JKuRbCXQMeVv0LFbztFg</recordid><startdate>201901</startdate><enddate>201901</enddate><creator>Shaik, Md Munan</creator><creator>Peng, Hanqin</creator><creator>Lu, Jianming</creator><creator>Rits-Volloch, Sophia</creator><creator>Xu, Chen</creator><creator>Liao, Maofu</creator><creator>Chen, Bing</creator><general>Nature Publishing Group UK</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>ATWCN</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7TG</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>BKSAR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</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>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PCBAR</scope><scope>PDBOC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>R05</scope><scope>RC3</scope><scope>S0X</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201901</creationdate><title>Structural basis of coreceptor recognition by HIV-1 envelope spike</title><author>Shaik, Md Munan ; Peng, Hanqin ; Lu, Jianming ; Rits-Volloch, Sophia ; Xu, Chen ; Liao, Maofu ; Chen, Bing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c738t-7e335e86941ae42c842fbfb4fca00d731e2302cb02ef27c3086c7c337b0570863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>101/28</topic><topic>631/535</topic><topic>631/535/1258/1259</topic><topic>82/83</topic><topic>Allosteric properties</topic><topic>Analysis</topic><topic>Anchoring</topic><topic>Anti-HIV Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shaik, Md Munan</au><au>Peng, Hanqin</au><au>Lu, Jianming</au><au>Rits-Volloch, Sophia</au><au>Xu, Chen</au><au>Liao, Maofu</au><au>Chen, Bing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis of coreceptor recognition by HIV-1 envelope spike</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2019-01</date><risdate>2019</risdate><volume>565</volume><issue>7739</issue><spage>318</spage><epage>323</epage><pages>318-323</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>HIV-1 envelope glycoprotein (Env), which consists of trimeric (gp160)
3
cleaved to (gp120 and gp41)
3
, interacts with the primary receptor CD4 and a coreceptor (such as chemokine receptor CCR5) to fuse viral and target-cell membranes. The gp120–coreceptor interaction has previously been proposed as the most crucial trigger for unleashing the fusogenic potential of gp41. Here we report a cryo-electron microscopy structure of a full-length gp120 in complex with soluble CD4 and unmodified human CCR5, at 3.9 Å resolution. The V3 loop of gp120 inserts into the chemokine-binding pocket formed by seven transmembrane helices of CCR5, and the N terminus of CCR5 contacts the CD4-induced bridging sheet of gp120. CCR5 induces no obvious allosteric changes in gp120 that can propagate to gp41; it does bring the Env trimer close to the target membrane. The N terminus of gp120, which is gripped by gp41 in the pre-fusion or CD4-bound Env, flips back in the CCR5-bound conformation and may irreversibly destabilize gp41 to initiate fusion. The coreceptor probably functions by stabilizing and anchoring the CD4-induced conformation of Env near the cell membrane. These results advance our understanding of HIV-1 entry into host cells and may guide the development of vaccines and therapeutic agents.
The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30542158</pmid><doi>10.1038/s41586-018-0804-9</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2019-01, Vol.565 (7739), p.318-323 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6391877 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | 101/28 631/535 631/535/1258/1259 82/83 Allosteric properties Analysis Anchoring Anti-HIV Agents - chemistry Anti-HIV Agents - metabolism Automation Binding Sites CCR5 protein CD4 antigen CD4 Antigens - chemistry CD4 Antigens - isolation & purification CD4 Antigens - metabolism CD4 Antigens - ultrastructure Cell Line Cell membranes Chemical compounds Chemokine CCL5 - chemistry Chemokine CCL5 - metabolism Chemokines Conformation Cryoelectron microscopy Electron microscopy Genetic aspects Glycoprotein gp120 Glycoprotein gp160 Glycoprotein gp41 Glycoproteins Helices HIV HIV Envelope Protein gp120 - chemistry HIV Envelope Protein gp120 - isolation & purification HIV Envelope Protein gp120 - metabolism HIV Envelope Protein gp120 - ultrastructure HIV Envelope Protein gp41 - chemistry HIV Envelope Protein gp41 - metabolism HIV Envelope Protein gp41 - ultrastructure Human immunodeficiency virus Humanities and Social Sciences Humans Inserts Ligands Maraviroc - chemistry Maraviroc - metabolism Membranes Microscopy Models, Molecular multidisciplinary Pharmacology Protein Binding Protein Conformation Protein structure Proteins Receptors, CCR5 - chemistry Receptors, CCR5 - isolation & purification Receptors, CCR5 - metabolism Receptors, CCR5 - ultrastructure Receptors, HIV - antagonists & inhibitors Receptors, HIV - chemistry Receptors, HIV - metabolism Receptors, HIV - ultrastructure Science Science (multidisciplinary) Signal transduction Structure Trimers Vaccines Viruses |
| title | Structural basis of coreceptor recognition by HIV-1 envelope spike |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T09%3A39%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structural%20basis%20of%20coreceptor%20recognition%20by%20HIV-1%20envelope%20spike&rft.jtitle=Nature%20(London)&rft.au=Shaik,%20Md%20Munan&rft.date=2019-01&rft.volume=565&rft.issue=7739&rft.spage=318&rft.epage=323&rft.pages=318-323&rft.issn=0028-0836&rft.eissn=1476-4687&rft_id=info:doi/10.1038/s41586-018-0804-9&rft_dat=%3Cgale_pubme%3EA573274091%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2171615963&rft_id=info:pmid/30542158&rft_galeid=A573274091&rfr_iscdi=true |