Structural basis of dimerization of chemokine receptors CCR5 and CXCR4
Abstract G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-42082-z |
| _version_ | 1797558554346913792 |
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| author | Daniele Di Marino Paolo Conflitti Stefano Motta Vittorio Limongelli |
| author_facet | Daniele Di Marino Paolo Conflitti Stefano Motta Vittorio Limongelli |
| author_sort | Daniele Di Marino |
| collection | DOAJ |
| description | Abstract G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4 by means of an advanced free-energy technique named coarse-grained metadynamics. Our results reproduce binding events between the GPCRs occurring in the minute timescale, revealing a symmetric and an asymmetric dimeric structure for each of the three investigated systems, CCR5/CCR5, CXCR4/CXCR4, and CCR5/CXCR4. The transmembrane helices TM4-TM5 and TM6-TM7 are the preferred binding interfaces for CCR5 and CXCR4, respectively. The identified dimeric states differ in the access to the binding sites of the ligand and G protein, indicating that dimerization may represent a fine allosteric mechanism to regulate receptor activity. Our study offers structural basis for the design of ligands able to modulate the formation of CCR5 and CXCR4 dimers and in turn their activity, with therapeutic potential against HIV, cancer, and immune-inflammatory diseases. |
| first_indexed | 2024-03-10T17:33:05Z |
| format | Article |
| id | doaj.art-ed387388cdd649dd94934622d941c9bf |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:33:05Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ed387388cdd649dd94934622d941c9bf2023-11-20T09:58:43ZengNature PortfolioNature Communications2041-17232023-10-0114111610.1038/s41467-023-42082-zStructural basis of dimerization of chemokine receptors CCR5 and CXCR4Daniele Di Marino0Paolo Conflitti1Stefano Motta2Vittorio Limongelli3Department of Life and Environmental Sciences - New York-Marche Structural Biology Centre (NY-MaSBiC), Polytechnic University of MarcheUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Euler InstituteDepartment of Earth and Environmental Sciences, University of Milano-BicoccaUniversità della Svizzera italiana (USI), Faculty of Biomedical Sciences, Euler InstituteAbstract G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4 by means of an advanced free-energy technique named coarse-grained metadynamics. Our results reproduce binding events between the GPCRs occurring in the minute timescale, revealing a symmetric and an asymmetric dimeric structure for each of the three investigated systems, CCR5/CCR5, CXCR4/CXCR4, and CCR5/CXCR4. The transmembrane helices TM4-TM5 and TM6-TM7 are the preferred binding interfaces for CCR5 and CXCR4, respectively. The identified dimeric states differ in the access to the binding sites of the ligand and G protein, indicating that dimerization may represent a fine allosteric mechanism to regulate receptor activity. Our study offers structural basis for the design of ligands able to modulate the formation of CCR5 and CXCR4 dimers and in turn their activity, with therapeutic potential against HIV, cancer, and immune-inflammatory diseases.https://doi.org/10.1038/s41467-023-42082-z |
| spellingShingle | Daniele Di Marino Paolo Conflitti Stefano Motta Vittorio Limongelli Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 Nature Communications |
| title | Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 |
| title_full | Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 |
| title_fullStr | Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 |
| title_full_unstemmed | Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 |
| title_short | Structural basis of dimerization of chemokine receptors CCR5 and CXCR4 |
| title_sort | structural basis of dimerization of chemokine receptors ccr5 and cxcr4 |
| url | https://doi.org/10.1038/s41467-023-42082-z |
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