Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor
Summary: Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and func...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719314457 |
| _version_ | 1818440812674940928 |
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| author | Xiaoyu Chen Yueming Xu Lu Qu Lijie Wu Gye Won Han Yu Guo Yiran Wu Qingtong Zhou Qianqian Sun Cenfeng Chu Jie Yang Liu Yang Quan Wang Shuguang Yuan Ling Wang Tao Hu Houchao Tao Yaping Sun Yunpeng Song Liaoyuan Hu Zhi-Jie Liu Raymond C. Stevens Suwen Zhao Dong Wu Guisheng Zhong |
| author_facet | Xiaoyu Chen Yueming Xu Lu Qu Lijie Wu Gye Won Han Yu Guo Yiran Wu Qingtong Zhou Qianqian Sun Cenfeng Chu Jie Yang Liu Yang Quan Wang Shuguang Yuan Ling Wang Tao Hu Houchao Tao Yaping Sun Yunpeng Song Liaoyuan Hu Zhi-Jie Liu Raymond C. Stevens Suwen Zhao Dong Wu Guisheng Zhong |
| author_sort | Xiaoyu Chen |
| collection | DOAJ |
| description | Summary: Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and function of β adrenergic receptors (βARs). However, the structure of α adrenergic receptors (αARs) remains to be determined. Here, we report the structure of the human α2C adrenergic receptor (α2CAR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α2CAR-specific D206ECL2-R409ECL3-Y4056.58 network plays a role in determining α2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α2CAR is involved in receptor activation. Together, our structure of human α2CAR-RS79948 provides key insight into the mechanism underlying the α2 adrenergic receptor activation and subtype selectivity. : Chen et al. report the crystal structure of human α2CAR and the functional experimental results, which indicate that extracellular regions determine α2 adrenergic subtype selectivity. The structural and functional results provide the molecular explanation for α2CAR selective ligands and insights to understand GPCR subtype selectivity. Keywords: α2C adrenergic receptor, subtype selectivity, crystal structure, GPCRs, Raynaud's syndrome, JP1302 |
| first_indexed | 2024-12-14T18:18:18Z |
| format | Article |
| id | doaj.art-47fe6739c20c4baf9693d9f56fa1dd29 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T18:18:18Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-47fe6739c20c4baf9693d9f56fa1dd292022-12-21T22:52:08ZengElsevierCell Reports2211-12472019-12-01291029362943.e4Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic ReceptorXiaoyu Chen0Yueming Xu1Lu Qu2Lijie Wu3Gye Won Han4Yu Guo5Yiran Wu6Qingtong Zhou7Qianqian Sun8Cenfeng Chu9Jie Yang10Liu Yang11Quan Wang12Shuguang Yuan13Ling Wang14Tao Hu15Houchao Tao16Yaping Sun17Yunpeng Song18Liaoyuan Hu19Zhi-Jie Liu20Raymond C. Stevens21Suwen Zhao22Dong Wu23Guisheng Zhong24iHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaDepartments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USAiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaShenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Laboratory of Biomodelling, Faculty of Chemistry & Biological and Chemical Research Centre, University of Warsaw, 02-093 Warsaw, PolandiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing 100049, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaAmgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, ChinaAmgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, ChinaAmgen Asia R&D Center, Amgen Biopharmaceutical R&D (Shanghai), Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authoriHuman Institute, ShanghaiTech University, Shanghai 201210, China; Corresponding authoriHuman Institute, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authorSummary: Adrenergic G-protein-coupled receptors (GPCRs) mediate different cellular signaling pathways in the presence of endogenous catecholamines and play important roles in both physiological and pathological conditions. Extensive studies have been carried out to investigate the structure and function of β adrenergic receptors (βARs). However, the structure of α adrenergic receptors (αARs) remains to be determined. Here, we report the structure of the human α2C adrenergic receptor (α2CAR) with the non-selective antagonist, RS79948, at 2.8 Å. Our structure, mutations, modeling, and functional experiments indicate that a α2CAR-specific D206ECL2-R409ECL3-Y4056.58 network plays a role in determining α2 adrenergic subtype selectivity. Furthermore, our results show that a specific loosened helix at the top of TM4 in α2CAR is involved in receptor activation. Together, our structure of human α2CAR-RS79948 provides key insight into the mechanism underlying the α2 adrenergic receptor activation and subtype selectivity. : Chen et al. report the crystal structure of human α2CAR and the functional experimental results, which indicate that extracellular regions determine α2 adrenergic subtype selectivity. The structural and functional results provide the molecular explanation for α2CAR selective ligands and insights to understand GPCR subtype selectivity. Keywords: α2C adrenergic receptor, subtype selectivity, crystal structure, GPCRs, Raynaud's syndrome, JP1302http://www.sciencedirect.com/science/article/pii/S2211124719314457 |
| spellingShingle | Xiaoyu Chen Yueming Xu Lu Qu Lijie Wu Gye Won Han Yu Guo Yiran Wu Qingtong Zhou Qianqian Sun Cenfeng Chu Jie Yang Liu Yang Quan Wang Shuguang Yuan Ling Wang Tao Hu Houchao Tao Yaping Sun Yunpeng Song Liaoyuan Hu Zhi-Jie Liu Raymond C. Stevens Suwen Zhao Dong Wu Guisheng Zhong Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor Cell Reports |
| title | Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor |
| title_full | Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor |
| title_fullStr | Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor |
| title_full_unstemmed | Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor |
| title_short | Molecular Mechanism for Ligand Recognition and Subtype Selectivity of α2C Adrenergic Receptor |
| title_sort | molecular mechanism for ligand recognition and subtype selectivity of α2c adrenergic receptor |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719314457 |
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