Ligand-Based NMR Study of C‑X‑C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells
Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent ana...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-04, Vol.61 (7), p.2910-2923 |
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| creator | Brancaccio, Diego Diana, Donatella Di Maro, Salvatore Di Leva, Francesco Saverio Tomassi, Stefano Fattorusso, Roberto Russo, Luigi Scala, Stefania Trotta, Anna Maria Portella, Luigi Novellino, Ettore Marinelli, Luciana Carotenuto, Alfonso |
| description | Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs. |
| doi_str_mv | 10.1021/acs.jmedchem.7b01830 |
| format | Article |
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The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b01830</identifier><identifier>PMID: 29522685</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Chemokine CXCL12 - antagonists & inhibitors ; Chemokine CXCL12 - metabolism ; Cricetinae ; Cricetulus ; Epitope Mapping ; Guanidine - metabolism ; Humans ; Leukemia, T-Cell - metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Conformation ; Molecular Dynamics Simulation ; Neoplasms - metabolism ; Receptors, CXCR4 - antagonists & inhibitors ; Receptors, CXCR4 - metabolism ; Receptors, G-Protein-Coupled - metabolism</subject><ispartof>Journal of medicinal chemistry, 2018-04, Vol.61 (7), p.2910-2923</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a414t-f178677b8d18545d84a4a144e9a21d548da266d0ca4294523c5d3135f7924ea83</citedby><cites>FETCH-LOGICAL-a414t-f178677b8d18545d84a4a144e9a21d548da266d0ca4294523c5d3135f7924ea83</cites><orcidid>0000-0002-2181-2142 ; 0000-0001-7532-5449 ; 0000-0002-3539-5343 ; 0000-0002-9286-4433 ; 0000-0002-4084-8044</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b01830$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01830$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27055,27903,27904,56715,56765</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29522685$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brancaccio, Diego</creatorcontrib><creatorcontrib>Diana, Donatella</creatorcontrib><creatorcontrib>Di Maro, Salvatore</creatorcontrib><creatorcontrib>Di Leva, Francesco Saverio</creatorcontrib><creatorcontrib>Tomassi, Stefano</creatorcontrib><creatorcontrib>Fattorusso, Roberto</creatorcontrib><creatorcontrib>Russo, Luigi</creatorcontrib><creatorcontrib>Scala, Stefania</creatorcontrib><creatorcontrib>Trotta, Anna Maria</creatorcontrib><creatorcontrib>Portella, Luigi</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Marinelli, Luciana</creatorcontrib><creatorcontrib>Carotenuto, Alfonso</creatorcontrib><title>Ligand-Based NMR Study of C‑X‑C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. 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Diana, Donatella ; Di Maro, Salvatore ; Di Leva, Francesco Saverio ; Tomassi, Stefano ; Fattorusso, Roberto ; Russo, Luigi ; Scala, Stefania ; Trotta, Anna Maria ; Portella, Luigi ; Novellino, Ettore ; Marinelli, Luciana ; Carotenuto, Alfonso</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a414t-f178677b8d18545d84a4a144e9a21d548da266d0ca4294523c5d3135f7924ea83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Chemokine CXCL12 - antagonists & inhibitors</topic><topic>Chemokine CXCL12 - metabolism</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Epitope Mapping</topic><topic>Guanidine - metabolism</topic><topic>Humans</topic><topic>Leukemia, T-Cell - metabolism</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Dynamics Simulation</topic><topic>Neoplasms - metabolism</topic><topic>Receptors, CXCR4 - antagonists & inhibitors</topic><topic>Receptors, CXCR4 - metabolism</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brancaccio, Diego</creatorcontrib><creatorcontrib>Diana, Donatella</creatorcontrib><creatorcontrib>Di Maro, Salvatore</creatorcontrib><creatorcontrib>Di Leva, Francesco Saverio</creatorcontrib><creatorcontrib>Tomassi, Stefano</creatorcontrib><creatorcontrib>Fattorusso, Roberto</creatorcontrib><creatorcontrib>Russo, Luigi</creatorcontrib><creatorcontrib>Scala, Stefania</creatorcontrib><creatorcontrib>Trotta, Anna Maria</creatorcontrib><creatorcontrib>Portella, Luigi</creatorcontrib><creatorcontrib>Novellino, Ettore</creatorcontrib><creatorcontrib>Marinelli, Luciana</creatorcontrib><creatorcontrib>Carotenuto, Alfonso</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brancaccio, Diego</au><au>Diana, Donatella</au><au>Di Maro, Salvatore</au><au>Di Leva, Francesco Saverio</au><au>Tomassi, Stefano</au><au>Fattorusso, Roberto</au><au>Russo, Luigi</au><au>Scala, Stefania</au><au>Trotta, Anna Maria</au><au>Portella, Luigi</au><au>Novellino, Ettore</au><au>Marinelli, Luciana</au><au>Carotenuto, Alfonso</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ligand-Based NMR Study of C‑X‑C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2018-04-12</date><risdate>2018</risdate><volume>61</volume><issue>7</issue><spage>2910</spage><epage>2923</epage><pages>2910-2923</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. 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| ispartof | Journal of medicinal chemistry, 2018-04, Vol.61 (7), p.2910-2923 |
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| subjects | Animals Cell Line Cell Line, Tumor Cell Survival Chemokine CXCL12 - antagonists & inhibitors Chemokine CXCL12 - metabolism Cricetinae Cricetulus Epitope Mapping Guanidine - metabolism Humans Leukemia, T-Cell - metabolism Magnetic Resonance Spectroscopy Models, Molecular Molecular Conformation Molecular Dynamics Simulation Neoplasms - metabolism Receptors, CXCR4 - antagonists & inhibitors Receptors, CXCR4 - metabolism Receptors, G-Protein-Coupled - metabolism |
| title | Ligand-Based NMR Study of C‑X‑C Chemokine Receptor Type 4 (CXCR4)–Ligand Interactions on Living Cancer Cells |
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