Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2
Abstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatm...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-11-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00610-7 |
| _version_ | 1797416153759350784 |
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| author | Xin Pan Fang Ye Peiruo Ning Zhiyi Zhang Xinyu Li Binghao Zhang Qian Wang Geng Chen Wei Gao Chen Qiu Zhangsong Wu Jiancheng Li Lizhe Zhu Jiang Xia Kaizheng Gong Yang Du |
| author_facet | Xin Pan Fang Ye Peiruo Ning Zhiyi Zhang Xinyu Li Binghao Zhang Qian Wang Geng Chen Wei Gao Chen Qiu Zhangsong Wu Jiancheng Li Lizhe Zhu Jiang Xia Kaizheng Gong Yang Du |
| author_sort | Xin Pan |
| collection | DOAJ |
| description | Abstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2–Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892–HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects. |
| first_indexed | 2024-03-09T05:59:41Z |
| format | Article |
| id | doaj.art-8c6f33326a9245ae978c5009f4185e6c |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-09T05:59:41Z |
| publishDate | 2023-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-8c6f33326a9245ae978c5009f4185e6c2023-12-03T12:10:16ZengNature Publishing GroupCell Discovery2056-59682023-11-019111710.1038/s41421-023-00610-7Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2Xin Pan0Fang Ye1Peiruo Ning2Zhiyi Zhang3Xinyu Li4Binghao Zhang5Qian Wang6Geng Chen7Wei Gao8Chen Qiu9Zhangsong Wu10Jiancheng Li11Lizhe Zhu12Jiang Xia13Kaizheng Gong14Yang Du15Kobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongWarshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongInstrumental Analysis Center, Shenzhen UniversityWarshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong KongDepartment of Chemistry, The Chinese University of Hong KongDepartment of Cardiology, Central Laboratory, The Affiliated Hospital of Yangzhou University, Yangzhou UniversityKobilka Institute of Innovative Drug Discovery, Shenzhen Futian Biomedical Innovation R&D Center, School of Medicine, The Chinese University of Hong KongAbstract Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of cardiovascular, neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2–Gi1 complexes with or without agonists, including the drugs niacin (2.69 Å) and acipimox (3.23 Å), the highly subtype-specific agonist MK-6892 (3.25 Å), and apo form (3.28 Å). Combined with molecular dynamics simulation and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892–HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which shed light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.https://doi.org/10.1038/s41421-023-00610-7 |
| spellingShingle | Xin Pan Fang Ye Peiruo Ning Zhiyi Zhang Xinyu Li Binghao Zhang Qian Wang Geng Chen Wei Gao Chen Qiu Zhangsong Wu Jiancheng Li Lizhe Zhu Jiang Xia Kaizheng Gong Yang Du Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 Cell Discovery |
| title | Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 |
| title_full | Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 |
| title_fullStr | Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 |
| title_full_unstemmed | Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 |
| title_short | Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2 |
| title_sort | structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor hcar2 |
| url | https://doi.org/10.1038/s41421-023-00610-7 |
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