Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding
Abstract Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Her...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41650-7 |
| _version_ | 1797558083095887872 |
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| author | Shota Suzuki Kotaro Tanaka Kouki Nishikawa Hiroshi Suzuki Atsunori Oshima Yoshinori Fujiyoshi |
| author_facet | Shota Suzuki Kotaro Tanaka Kouki Nishikawa Hiroshi Suzuki Atsunori Oshima Yoshinori Fujiyoshi |
| author_sort | Shota Suzuki |
| collection | DOAJ |
| description | Abstract Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms. |
| first_indexed | 2024-03-10T17:25:26Z |
| format | Article |
| id | doaj.art-84bdb686a8d447adb1d134ac1866c6f1 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:25:26Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-84bdb686a8d447adb1d134ac1866c6f12023-11-20T10:12:03ZengNature PortfolioNature Communications2041-17232023-09-0114111310.1038/s41467-023-41650-7Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand bindingShota Suzuki0Kotaro Tanaka1Kouki Nishikawa2Hiroshi Suzuki3Atsunori Oshima4Yoshinori Fujiyoshi5TMDU Advanced Research Institute, Tokyo Medical and Dental University Bunkyo-kuCellular and Structural Physiology Institute (CeSPI), Nagoya UniversityJoint Research Course for Advanced Biomolecular Characterization, Tokyo University of Agriculture and TechnologyTMDU Advanced Research Institute, Tokyo Medical and Dental University Bunkyo-kuCellular and Structural Physiology Institute (CeSPI), Nagoya UniversityTMDU Advanced Research Institute, Tokyo Medical and Dental University Bunkyo-kuAbstract Hydroxycarboxylic acid receptors (HCA) are expressed in various tissues and immune cells. HCA2 and its agonist are thus important targets for treating inflammatory and metabolic disorders. Only limited information is available, however, on the active-state binding of HCAs with agonists. Here, we present cryo-EM structures of human HCA2-Gi and HCA3-Gi signaling complexes binding with multiple compounds bound. Agonists were revealed to form a salt bridge with arginine, which is conserved in the HCA family, to activate these receptors. Extracellular regions of the receptors form a lid-like structure that covers the ligand-binding pocket. Although transmembrane (TM) 6 in HCAs undergoes dynamic conformational changes, ligands do not directly interact with amino acids in TM6, suggesting that indirect signaling induces a slight shift in TM6 to activate Gi proteins. Structural analyses of agonist-bound HCA2 and HCA3 together with mutagenesis and molecular dynamics simulation provide molecular insights into HCA ligand recognition and activation mechanisms.https://doi.org/10.1038/s41467-023-41650-7 |
| spellingShingle | Shota Suzuki Kotaro Tanaka Kouki Nishikawa Hiroshi Suzuki Atsunori Oshima Yoshinori Fujiyoshi Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding Nature Communications |
| title | Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| title_full | Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| title_fullStr | Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| title_full_unstemmed | Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| title_short | Structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| title_sort | structural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding |
| url | https://doi.org/10.1038/s41467-023-41650-7 |
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