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Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists

文献类型：期刊论文

作者Li, Jingru4,5; You, Chongzhao3,4; Li, Yang3,4; Li, Changyao1,2,4; Fan, Wenjia4,5; Chen, Zecai3,4; Hu, Wen4; Wu, Kai4; Xu, H. Eric3,4,5; Zhao, Li-Hua3,4
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2024-06-25
卷号121期号:26页码:10
关键词SSTR5 peptide agonists agonist selectivity receptor activation
ISSN号0027-8424
DOI10.1073/pnas.2321710121
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhao, Li-Hua(zhaolihuawendy@simm.ac.cn)
英文摘要Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high- resolution cryogenicelectron microscope structures of the SSTR5-Gi complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 & Aring; and 2.9 & Aring;, respectively. The structures reveal that binding of these peptides causes rearrangement of a "hydrophobic lock", consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling G alpha i protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure - based drug development targeting this therapeutically relevant receptor.
WOS关键词SMOOTH-MUSCLE-CELLS ; MOLECULAR PHARMACOLOGY ; EXPRESSION ; ANALOG ; PROLIFERATION ; VISUALIZATION ; SECRETION ; SUBTYPES ; BIOLOGY ; SYSTEM
资助项目Natural Science Foundation of Shanghai[23ZR1475200] ; National Natural Science Foundation of China[32071203] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; National Key R&D Program of China[2022YFC2703105] ; National Key R&D Program of China[2019YFA0904200] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Shanghai Municipal Science and Technology Major Project ; Young Innovator Association of CAS[Y2022078] ; Lingang Laboratory[LG-GG-202204-01] ; State Key Laboratory of Drug Research[SKLDR-2023-TT-04]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001255071700004
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/312038]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Zhao, Li-Hua
作者单位1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Lingang Lab, Shanghai 200031, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
推荐引用方式
GB/T 7714		 Li, Jingru,You, Chongzhao,Li, Yang,et al. Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2024,121(26):10.
APA Li, Jingru.,You, Chongzhao.,Li, Yang.,Li, Changyao.,Fan, Wenjia.,...&Zhao, Li-Hua.(2024).Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121(26),10.
MLA Li, Jingru,et al."Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121.26(2024):10.

入库方式： OAI收割

来源：上海药物研究所

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