Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins
文献类型：期刊论文
| 作者 | Cong, Zhaotong7; Zhao, Fenghui5,6; Li, Yang4; Luo, Gan3; Mai, Yiting2; Chen, Xianyue2; Chen, Yanyan2; Lin, Shi2; Cai, Xiaoqing5,6; Zhou, Qingtong2,7 |
| 刊名 | CELL DISCOVERY
 |
| 出版日期 | 2024-02-13 |
| 卷号 | 10期号:1页码:13 |
| DOI | 10.1038/s41421-024-00649-0 |
| 通讯作者 | Zhou, Qingtong(zhouqt@fudan.edu.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) |
| 英文摘要 | Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade of signaling events leading to the formation of an active agonist-receptor-G protein complex. However, intracellular signal transducers can also activate the receptor independent of extracellular stimuli, suggesting an intrinsic role of G proteins in this process. Here, we report cryo-electron microscopy structures of the human GLP-1 receptor (GLP-1R), GCG receptor (GCGR), and GIP receptor (GIPR) in complex with G(s) proteins without the presence of cognate ligands. These ligand-free complexes share a similar intracellular architecture to those bound by endogenous peptides, in which, the G(s) protein alone directly opens the intracellular binding cavity and rewires the extracellular orthosteric pocket to stabilize the receptor in a state unseen before. While the peptide-binding site is partially occupied by the inward folded transmembrane helix 6 (TM6)-extracellular loop 3 (ECL3) juncture of GIPR or a segment of GCGR ECL2, the extracellular portion of GLP-1R adopts a conformation close to the active state. Our findings offer valuable insights into the distinct activation mechanisms of these three important receptors. It is possible that in the absence of a ligand, the intracellular half of transmembrane domain is mobilized with the help of G(s) protein, which in turn rearranges the extracellular half to form a transitional conformation, facilitating the entry of the peptide N-terminus. |
| WOS关键词 | CRYO-EM STRUCTURE ; CRYSTAL-STRUCTURE ; STRUCTURAL BASIS ; GPCR ACTIVATION ; RECEPTOR ; PEPTIDE ; RECOGNITION ; MECHANISMS ; BINDING |
| 资助项目 | National Natural Science Foundation of China (National Science Foundation of China) ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[81872915] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[82073904] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[82273961] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[82273985] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[82121005] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[81973373] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[32200576] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[82204474] ; National Natural Science Foundation of China[2022M710806] ; National Natural Science Foundation of China[2022M713266] ; Postdoctoral Science Foundation of China[BX20220070] ; Postdoctoral Innovative Talent Support Plan of China[2018ZX09735-001] ; Postdoctoral Innovative Talent Support Plan of China[2018ZX09711002-002-005] ; Postdoctoral Innovative Talent Support Plan of China[2021ZD0203400] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018YFA0507000] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2023YFA1800804] ; National Key Basic Research Program of China[ZDKJ2021028] ; Hainan Provincial Major Science and Technology Project[21JC1401600] ; Shanghai Municipality Science and Technology Development Fund[23XD1400900] ; Program of Shanghai Academic/Technology Research Leader |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| 出版者 | SPRINGERNATURE |
| WOS记录号 | WOS:001160694400002 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309237]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhou, Qingtong; Yang, Dehua; Wang, Ming-Wei |
| 作者单位 | 1.Hainan Med Univ, Sch Pharm, Haikou, Hainan, Peoples R China 2.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R China 3.Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol MOE NHC CAMS, Shanghai, Peoples R China 4.Fudan Univ, Shanghai Inst Infect Dis & Biosecur, Sch Basic Med Sci, Dept Med Microbiol & Parasitol, Shanghai, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China 7.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China 8.Univ Tokyo, Sch Sci, Dept Chem, Tokyo, Japan |
| 推荐引用方式 GB/T 7714 | Cong, Zhaotong,Zhao, Fenghui,Li, Yang,et al. Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins[J]. CELL DISCOVERY,2024,10(1):13. |
| APA | Cong, Zhaotong.,Zhao, Fenghui.,Li, Yang.,Luo, Gan.,Mai, Yiting.,...&Wang, Ming-Wei.(2024).Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins.CELL DISCOVERY,10(1),13. |
| MLA | Cong, Zhaotong,et al."Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins".CELL DISCOVERY 10.1(2024):13. |
入库方式： OAI收割
来源：上海药物研究所
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