Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
文献类型：期刊论文
| 作者 | Cong, Zhaotong1,2; Chen, Li-Nan3; Ma, Honglei2; Zhou, Qingtong4; Zou, Xinyu1,5; Ye, Chenyu2; Dai, Antao6; Liu, Qing6; Huang, Wei7; Sun, Xianqiang7 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2021-06-18 |
| 卷号 | 12期号:1页码:11 |
| ISSN号 | 2041-1723 |
| DOI | 10.1038/s41467-021-24058-z |
| 通讯作者 | Yang, Dehua(dhyang@simm.ac.cn) ; Eric Xu, H.(eric.xu@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) |
| 英文摘要 | The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G(s). The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric G(s) which offers insights into the molecular details of ago-allosterism. |
| WOS关键词 | CRYO-EM STRUCTURE ; GLP-1 RECEPTOR ; CRYSTAL-STRUCTURE ; ACTIVATION ; MECHANISM ; AGONISTS ; COMPLEX ; FAMILY ; DOMAIN |
| 资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science and Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2018YFA0507000] ; National Key Basic Research Program of China[2019YFA0508800] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Ministry of Science and Technology of China Major Project[XDB08020303] ; Shanghai Municipal Science and Technology Commission[19ZR1467500] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; Fundamental Research Funds for Central Universities[2019XZZX001-01-06] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; Young Innovator Association of CAS Enrollment ; SA-SIBS Scholarship Program |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000665038900031 |
| 出版者 | NATURE RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296833]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Yang, Dehua; Eric Xu, H.; Zhang, Yan; Wang, Ming-Wei |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Shanghai, Peoples R China 2.Shanghai Inst Mat Med, Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Zhejiang Univ, Dept Biophys, Sch Med, Dept Pathol Sir Run Run Shaw Hosp, Hangzhou, Peoples R China 4.Fudan Univ, Sch Basic Med Sci, Shanghai, Peoples R China 5.Huazhong Univ Sci & Technol, Sch Artificial Intelligence & Automat, Wuhan, Peoples R China 6.Shanghai Inst Mat Med, Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai, Peoples R China 7.Qilu Regor Therapeutics Inc, Shanghai, Peoples R China 8.Univ Chinese Acad Sci, Beijing, Peoples R China 9.Zhejiang Univ Sch Med, MOE Frontier Sci Ctr, Brain Res & BrainMachine Integrat, Hangzhou, Peoples R China 10.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cong, Zhaotong,Chen, Li-Nan,Ma, Honglei,et al. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor[J]. NATURE COMMUNICATIONS,2021,12(1):11. |
| APA | Cong, Zhaotong.,Chen, Li-Nan.,Ma, Honglei.,Zhou, Qingtong.,Zou, Xinyu.,...&Wang, Ming-Wei.(2021).Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.NATURE COMMUNICATIONS,12(1),11. |
| MLA | Cong, Zhaotong,et al."Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor".NATURE COMMUNICATIONS 12.1(2021):11. |
入库方式： OAI收割
来源：上海药物研究所
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