Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84
Abstract GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gαi protein-coupled human GPR84 bound to a synt...
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| Format: | Article |
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Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38985-6 |
| _version_ | 1797784568209604608 |
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| author | Heng Liu Qing Zhang Xinheng He Mengting Jiang Siwei Wang Xiaoci Yan Xi Cheng Yang Liu Fa-Jun Nan H. Eric Xu Xin Xie Wanchao Yin |
| author_facet | Heng Liu Qing Zhang Xinheng He Mengting Jiang Siwei Wang Xiaoci Yan Xi Cheng Yang Liu Fa-Jun Nan H. Eric Xu Xin Xie Wanchao Yin |
| author_sort | Heng Liu |
| collection | DOAJ |
| description | Abstract GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gαi protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and Gαi-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84. |
| first_indexed | 2024-03-13T00:41:45Z |
| format | Article |
| id | doaj.art-93122ec4fc19412c942ed11b75e97520 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T00:41:45Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
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| spelling | doaj.art-93122ec4fc19412c942ed11b75e975202023-07-09T11:17:56ZengNature PortfolioNature Communications2041-17232023-06-0114111410.1038/s41467-023-38985-6Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84Heng Liu0Qing Zhang1Xinheng He2Mengting Jiang3Siwei Wang4Xiaoci Yan5Xi Cheng6Yang Liu7Fa-Jun Nan8H. Eric Xu9Xin Xie10Wanchao Yin11State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesSchool of Chinese Materia Medica, Nanjing University of Chinese MedicineState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gαi protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and Gαi-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84.https://doi.org/10.1038/s41467-023-38985-6 |
| spellingShingle | Heng Liu Qing Zhang Xinheng He Mengting Jiang Siwei Wang Xiaoci Yan Xi Cheng Yang Liu Fa-Jun Nan H. Eric Xu Xin Xie Wanchao Yin Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 Nature Communications |
| title | Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 |
| title_full | Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 |
| title_fullStr | Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 |
| title_full_unstemmed | Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 |
| title_short | Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 |
| title_sort | structural insights into ligand recognition and activation of the medium chain fatty acid sensing receptor gpr84 |
| url | https://doi.org/10.1038/s41467-023-38985-6 |
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