Structural basis for signal recognition and transduction by platelet-activating-factor receptor
Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here...
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| Veröffentlicht in: | Nature structural & molecular biology 2018-06, Vol.25 (6), p.488-495 |
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| creator | Cao, Can Tan, Qiuxiang Xu, Chanjuan He, Lingli Yang, Linlin Zhou, Ye Zhou, Yiwei Qiao, Anna Lu, Minmin Yi, Cuiying Han, Gye Won Wang, Xianping Li, Xuemei Yang, Huaiyu Rao, Zihe Jiang, Hualiang Zhao, Yongfang Liu, Jianfeng Stevens, Raymond C. Zhao, Qiang Zhang, Xuejun C. Wu, Beili |
| description | Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR–SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.
Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle. |
| doi_str_mv | 10.1038/s41594-018-0068-y |
| format | Article |
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Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle.</description><identifier>ISSN: 1545-9993</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/s41594-018-0068-y</identifier><identifier>PMID: 29808000</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13/1 ; 13/95 ; 14/34 ; 38/70 ; 42/109 ; 45/77 ; 631/45/535/1266 ; 631/45/612/1237 ; 631/45/612/194 ; 631/80/86 ; 82/16 ; 82/80 ; 82/83 ; Antagonists (Biochemistry) ; Asthma ; Binding Sites ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Biophysics ; Cardiovascular diseases ; Cell interactions ; Cell receptors ; Cellular signal transduction ; Composition ; Crystal structure ; Crystallography, X-Ray ; Fluorescence Resonance Energy Transfer ; G protein-coupled receptors ; G proteins ; Health aspects ; Heart diseases ; Helices ; Humans ; Hydrogen Bonding ; Imidazoles - pharmacology ; Indoles - pharmacology ; Inflammation ; Laboratories ; Life Sciences ; Ligands ; Membrane Biology ; Molecular biology ; Molecular docking ; Molecular Docking Simulation ; Mutation ; Observations ; Phospholipids ; Physiological effects ; Platelet activating factor ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Membrane Glycoproteins - agonists ; Platelet Membrane Glycoproteins - antagonists & inhibitors ; Platelet Membrane Glycoproteins - chemistry ; Platelet Membrane Glycoproteins - metabolism ; Protein Conformation ; Protein Structure ; Proteins ; Receptors ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - antagonists & inhibitors ; Receptors, G-Protein-Coupled - chemistry ; Receptors, G-Protein-Coupled - metabolism ; Recognition ; Signal Transduction ; Structure ; Thiazoles - pharmacology</subject><ispartof>Nature structural & molecular biology, 2018-06, Vol.25 (6), p.488-495</ispartof><rights>The Author(s) 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jun 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c539t-888d4b1211f7b376196a8198995aaf01f5c7c90bcefd0e590bc8517a881a68553</citedby><cites>FETCH-LOGICAL-c539t-888d4b1211f7b376196a8198995aaf01f5c7c90bcefd0e590bc8517a881a68553</cites><orcidid>0000-0003-1751-7201 ; 0000-0002-4522-8725 ; 0000-0002-1936-0909</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/s41594-018-0068-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41594-018-0068-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29808000$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Can</creatorcontrib><creatorcontrib>Tan, Qiuxiang</creatorcontrib><creatorcontrib>Xu, Chanjuan</creatorcontrib><creatorcontrib>He, Lingli</creatorcontrib><creatorcontrib>Yang, Linlin</creatorcontrib><creatorcontrib>Zhou, Ye</creatorcontrib><creatorcontrib>Zhou, Yiwei</creatorcontrib><creatorcontrib>Qiao, Anna</creatorcontrib><creatorcontrib>Lu, Minmin</creatorcontrib><creatorcontrib>Yi, Cuiying</creatorcontrib><creatorcontrib>Han, Gye Won</creatorcontrib><creatorcontrib>Wang, Xianping</creatorcontrib><creatorcontrib>Li, Xuemei</creatorcontrib><creatorcontrib>Yang, Huaiyu</creatorcontrib><creatorcontrib>Rao, Zihe</creatorcontrib><creatorcontrib>Jiang, Hualiang</creatorcontrib><creatorcontrib>Zhao, Yongfang</creatorcontrib><creatorcontrib>Liu, Jianfeng</creatorcontrib><creatorcontrib>Stevens, Raymond C.</creatorcontrib><creatorcontrib>Zhao, Qiang</creatorcontrib><creatorcontrib>Zhang, Xuejun C.</creatorcontrib><creatorcontrib>Wu, Beili</creatorcontrib><title>Structural basis for signal recognition and transduction by platelet-activating-factor receptor</title><title>Nature structural & molecular biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Mol Biol</addtitle><description>Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR–SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.
Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle.</description><subject>13/1</subject><subject>13/95</subject><subject>14/34</subject><subject>38/70</subject><subject>42/109</subject><subject>45/77</subject><subject>631/45/535/1266</subject><subject>631/45/612/1237</subject><subject>631/45/612/194</subject><subject>631/80/86</subject><subject>82/16</subject><subject>82/80</subject><subject>82/83</subject><subject>Antagonists (Biochemistry)</subject><subject>Asthma</subject><subject>Binding Sites</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Biophysics</subject><subject>Cardiovascular diseases</subject><subject>Cell interactions</subject><subject>Cell receptors</subject><subject>Cellular signal 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pharmacology</subject><subject>Platelet Membrane Glycoproteins - agonists</subject><subject>Platelet Membrane Glycoproteins - antagonists & inhibitors</subject><subject>Platelet Membrane Glycoproteins - chemistry</subject><subject>Platelet Membrane Glycoproteins - metabolism</subject><subject>Protein Conformation</subject><subject>Protein Structure</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - antagonists & inhibitors</subject><subject>Receptors, G-Protein-Coupled - chemistry</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Recognition</subject><subject>Signal Transduction</subject><subject>Structure</subject><subject>Thiazoles - 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Biol</addtitle><date>2018-06-01</date><risdate>2018</risdate><volume>25</volume><issue>6</issue><spage>488</spage><epage>495</epage><pages>488-495</pages><issn>1545-9993</issn><eissn>1545-9985</eissn><abstract>Platelet-activating-factor receptor (PAFR) responds to platelet-activating factor (PAF), a phospholipid mediator of cell-to-cell communication that exhibits diverse physiological effects. PAFR is considered an important drug target for treating asthma, inflammation and cardiovascular diseases. Here we report crystal structures of human PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491 at 2.8-Å and 2.9-Å resolution, respectively. The structures, supported by molecular docking of PAF, provide insights into the signal-recognition mechanisms of PAFR. The PAFR–SR 27417 structure reveals an unusual conformation showing that the intracellular tips of helices II and IV shift outward by 13 Å and 4 Å, respectively, and helix VIII adopts an inward conformation. The PAFR structures, combined with single-molecule FRET and cell-based functional assays, suggest that the conformational change in the helical bundle is ligand dependent and plays a critical role in PAFR activation, thus greatly extending knowledge about signaling by G-protein-coupled receptors.
Crystal structures of PAFR in complex with the antagonist SR 27417 and the inverse agonist ABT-491, together with accompanying experiments, provide insight into recognition of PAF and reveal an unusual ligand-dependent conformation of helical bundle.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>29808000</pmid><doi>10.1038/s41594-018-0068-y</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0003-1751-7201</orcidid><orcidid>https://orcid.org/0000-0002-4522-8725</orcidid><orcidid>https://orcid.org/0000-0002-1936-0909</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1545-9993 |
| ispartof | Nature structural & molecular biology, 2018-06, Vol.25 (6), p.488-495 |
| issn | 1545-9993 1545-9985 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2046605744 |
| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | 13/1 13/95 14/34 38/70 42/109 45/77 631/45/535/1266 631/45/612/1237 631/45/612/194 631/80/86 82/16 82/80 82/83 Antagonists (Biochemistry) Asthma Binding Sites Biochemistry Biological Microscopy Biomedical and Life Sciences Biophysics Cardiovascular diseases Cell interactions Cell receptors Cellular signal transduction Composition Crystal structure Crystallography, X-Ray Fluorescence Resonance Energy Transfer G protein-coupled receptors G proteins Health aspects Heart diseases Helices Humans Hydrogen Bonding Imidazoles - pharmacology Indoles - pharmacology Inflammation Laboratories Life Sciences Ligands Membrane Biology Molecular biology Molecular docking Molecular Docking Simulation Mutation Observations Phospholipids Physiological effects Platelet activating factor Platelet Aggregation Inhibitors - pharmacology Platelet Membrane Glycoproteins - agonists Platelet Membrane Glycoproteins - antagonists & inhibitors Platelet Membrane Glycoproteins - chemistry Platelet Membrane Glycoproteins - metabolism Protein Conformation Protein Structure Proteins Receptors Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - chemistry Receptors, G-Protein-Coupled - metabolism Recognition Signal Transduction Structure Thiazoles - pharmacology |
| title | Structural basis for signal recognition and transduction by platelet-activating-factor receptor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T02%3A51%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structural%20basis%20for%20signal%20recognition%20and%20transduction%20by%20platelet-activating-factor%20receptor&rft.jtitle=Nature%20structural%20&%20molecular%20biology&rft.au=Cao,%20Can&rft.date=2018-06-01&rft.volume=25&rft.issue=6&rft.spage=488&rft.epage=495&rft.pages=488-495&rft.issn=1545-9993&rft.eissn=1545-9985&rft_id=info:doi/10.1038/s41594-018-0068-y&rft_dat=%3Cgale_proqu%3EA593382274%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2188969352&rft_id=info:pmid/29808000&rft_galeid=A593382274&rfr_iscdi=true |