Conserved class B GPCR activation by a biased intracellular agonist
文献类型：期刊论文
| 作者 | Zhao, Li-Hua1,2; He, Qian1,2 ; Yuan, Qingning1; Gu, Yimin1,2; He, Xinheng1,2; Shan, Hong1; Li, Junrui1; Wang, Kai1; Li, Yang1,2; Hu, Wen1
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| 刊名 | NATURE
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| 出版日期 | 2023-07-31 |
| 页码 | 25 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-023-06467 |
| 通讯作者 | Zhao, Li-Hua(zhaolihuawendy@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) |
| 英文摘要 | Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets1-5. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development6,7. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (Gs) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with Gs. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications. A study reports an orally available small-molecule agonist that binds between a G protein and its receptor, and characterizes this new binding mode. |
| WOS关键词 | GLP-1 RECEPTOR ; RECOGNITION ; MECHANISM ; PEPTIDE |
| 资助项目 | Chinese Academy of Sciences (CAS)[2018325] ; CAS Strategic Priority Research Program[Y2022078] ; CAS Strategic Priority Research Program[2019282] ; CAS Strategic Priority Research Program[32071203] ; Young Innovator Association of the CAS[32130022] ; Young Innovator Association of the CAS[82121005] ; Young Innovator Association of the CAS[2019YFA0904200] ; National Natural Science Foundation of China[2019SHZDZX02] ; National Key Ramp;amp;D Program of China ; SA-SIBS Scholarship Program[23ZR1475200] ; SA-SIBS Scholarship Program[SKLDR-2023-TT-04] ; Shanghai Municipal Science and Technology Major Project ; State Key Laboratory of Drug Research ; [XDB37030103] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PORTFOLIO |
| WOS记录号 | WOS:001059705400001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/307061]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Li-Hua; Xu, H. Eric |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, State Key Lab Drug Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Li-Hua,He, Qian,Yuan, Qingning,et al. Conserved class B GPCR activation by a biased intracellular agonist[J]. NATURE,2023:25. |
| APA | Zhao, Li-Hua.,He, Qian.,Yuan, Qingning.,Gu, Yimin.,He, Xinheng.,...&Xu, H. Eric.(2023).Conserved class B GPCR activation by a biased intracellular agonist.NATURE,25. |
| MLA | Zhao, Li-Hua,et al."Conserved class B GPCR activation by a biased intracellular agonist".NATURE (2023):25. |
入库方式： OAI收割
来源：上海药物研究所
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