Structural basis for the tethered peptide activation of adhesion GPCRs
文献类型：期刊论文
| 作者 | Ping, Yu-Qi2,3,4,5; Xiao, Peng2,6; Yang, Fan2,4,6,7; Zhao, Ru-Jia2,4; Guo, Sheng-Chao2; Yan, Xu4; Wu, Xiang2; Zhang, Chao2; Lu, Yan2; Zhao, Fenghui8 |
| 刊名 | NATURE
 |
| 出版日期 | 2022-04-13 |
| 页码 | 41 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-022-04619-y |
| 通讯作者 | Liebscher, Ines(Ines.Liebscher@medizin.uni-Leipzig.de) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Sun, Jin-Peng(sunjinpeng@sdu.edu.cn) |
| 英文摘要 | Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes(1-6). Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence(7)(-1)(2). Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G(s): GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an alpha-helical-bulge-beta-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W-6.53 and the constitution of a hydrogen-bond network formed by Q(7.49)/Y-7.49 and the P-6.47/V-6.47 phi phi G(6.50) motif (phi indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G(s)-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G(s). Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G(s) coupling. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; AGONIST ; GPR56/ADGRG1 ; EXPOSURE ; GROMACS ; CHIMERA ; GPR126 ; DOMAIN |
| 资助项目 | National Key Research and Development Program of China[2018YFC1003600] ; National Key Research and Development Program of China[2019YFA0904200] ; National Key Research and Development Program of China[2018YFA0507002] ; National Science Fund for Distinguished Young Scholars Grant[81825022] ; National Science Fund for Excellent Young Scholars[82122070] ; Shandong Provincial Natural Science Fund for Excellent Young Scholars[ZR2021YQ18] ; National Natural Science Foundation of China[81773704] ; National Natural Science Foundation of China[31971195] ; National Natural Science Foundation of China[31900936] ; National Natural Science Foundation of China[31770796] ; Key Research Project of the Natural Science Foundation of Beijing, China[Z200019] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; Key Research and Development Program of Shandong Province[2021CXGC011105] ; Key Research and Development Program of Shandong Province[GG201709260059] ; Key Research and Development Program of Shandong Province[2021ZLGX02] ; Shandong Provincial Natural Science Foundation[ZR2020ZD39] ; Shandong Provincial Natural Science Foundation[ZR2016CQ07] ; German Research Foundation[CRC1052] ; German Research Foundation[CRC1423] ; German Research Foundation[209933838] ; German Research Foundation[421152132] ; COST Association (COST Action)[CA18240] ; Fundamental Research Funds for the Central Universities[2021JCG020] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PORTFOLIO |
| WOS记录号 | WOS:000782392700011 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/299749]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liebscher, Ines; Xu, H. Eric; Sun, Jin-Peng |
| 作者单位 | 1.Binzhou Med Univ, Sch Pharm, Yantai, Peoples R China 2.Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Expt Teratol Mini, Jinan, Peoples R China 3.Chinese Acad Sci, Ctr Struct & Funct Drug Targets, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 4.Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Physiol,Key Lab Expt Teratol Minist Educ, Jinan, Peoples R China 5.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci Minist Educ, Beijing, Peoples R China 6.Shandong Univ, Hosp 2, Cheeloo Coll Med, Dept Clin Lab, Jinan, Peoples R China 7.Shandong Univ, Adv Med Res Inst, Jinan, Peoples R China 8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China 9.Shandong Univ, Cheeloo Coll Med, Sch Pharm, Jinan, Peoples R China 10.Univ Sci & Technol China, Sch Life Sci, Hefei, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ping, Yu-Qi,Xiao, Peng,Yang, Fan,et al. Structural basis for the tethered peptide activation of adhesion GPCRs[J]. NATURE,2022:41. |
| APA | Ping, Yu-Qi.,Xiao, Peng.,Yang, Fan.,Zhao, Ru-Jia.,Guo, Sheng-Chao.,...&Sun, Jin-Peng.(2022).Structural basis for the tethered peptide activation of adhesion GPCRs.NATURE,41. |
| MLA | Ping, Yu-Qi,et al."Structural basis for the tethered peptide activation of adhesion GPCRs".NATURE (2022):41. |
入库方式： OAI收割
来源：上海药物研究所
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