Structural insights into antagonist recognition by the vasopressin V2 receptor
文献类型：期刊论文
| 作者 | Zhang, Tianwei1,2; Liu, Hongli3; You, Chongzhao4; Zhang, Yixiao3; Xu, Youwei4; Pan, Benxun1; Wu, Canrong5; Jin, Sanshan1,2; Yin, Yu-Ling1; Wu, Kai6 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2025-11-04 |
| 卷号 | 16期号:1页码:10 |
| DOI | 10.1038/s41467-025-64735-x |
| 英文摘要 | The vasopressin V2 receptor (V2R), a class A G protein-coupled receptor, is essential for regulating body water homeostasis. V2R antagonists have emerged as promising treatments for hyponatremia; however, the absence of structural information for antagonist-bound V2R hampers our understanding of antagonist recognition and the targeted design of V2R antagonists. In this study, we present two cryo-electron microscopy structures of inactive V2R bound to the clinically approved antagonists tolvaptan and conivaptan. Combined with functional analyses and molecular dynamic simulations, these structures reveal distinct binding poses: tolvaptan is deeply inserted within the binding pocket, whereas conivaptan is positioned at a shallower depth. Integrated analyses further define critical pharmacophoric features governing antagonist activity and unveil a TM7 helical conformation-dependent antagonism mechanism that is distinct from classical GPCR inactivation modes. Our findings deepen understanding of antagonist recognition and antagonism of V2R, providing a foundation for the development of V2R-targeted therapies. |
| WOS关键词 | MOLECULAR-DYNAMICS ; TOLVAPTAN ; SOFTWARE ; SYSTEM ; POTENT ; MOTION ; TOOLS |
| 资助项目 | National Key Research and Development Program of China[2023YFC3605500] ; National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[22077110] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[22107090] ; National Key R&D Program of China[2022YFC2703105] ; Program of Shanghai Academic/Technology Research Leader[22XD1425200] ; Shanghai Oriental Talents Program ; Jiangsu Outstanding Youth Fund[BK20240051] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; China Postdoctoral Science Foundation[2023M731487] ; Shanghai Post-doctoral Excellence Program[2023018] ; Shanghai Post-doctoral Excellence Program[2022232] ; Shanghai Sailing Program[23YF1460700] ; Shanghai Sailing Program[22YF1461200] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001608931300036 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/319800]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Xu, H. Eric; Guo, Dong; Jiang, Yi |
| 作者单位 | 1.Lingang Lab, Shanghai, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 3.Xuzhou Med Univ, Clin Pharm, Jiangsu Key Lab New Drug Res, Xuzhou, Jiangsu, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Materia Med, State Key Lab Drug Res, Shanghai, Peoples R China 5.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, Ruijin Hosp,State Key Lab Med Genom,Sch Med, Shanghai, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Materia Med, Shanghai Adv Electron Microscope Ctr, Shanghai, Peoples R China 7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Materia Med, Zhongshan, Guangdong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Tianwei,Liu, Hongli,You, Chongzhao,et al. Structural insights into antagonist recognition by the vasopressin V2 receptor[J]. NATURE COMMUNICATIONS,2025,16(1):10. |
| APA | Zhang, Tianwei.,Liu, Hongli.,You, Chongzhao.,Zhang, Yixiao.,Xu, Youwei.,...&Jiang, Yi.(2025).Structural insights into antagonist recognition by the vasopressin V2 receptor.NATURE COMMUNICATIONS,16(1),10. |
| MLA | Zhang, Tianwei,et al."Structural insights into antagonist recognition by the vasopressin V2 receptor".NATURE COMMUNICATIONS 16.1(2025):10. |
入库方式： OAI收割
来源：上海药物研究所
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