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Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3

文献类型：期刊论文

作者Wang, Yujue1,2,4; Xu, Youwei5; Wang, Yue5; Zhang, Jie1,2,4; Chen, Lan1,2,4; He, Xinheng5,6; Fan, Wenjia5,8; Wu, Kai3; Hu, Wen3; Cheng, Xi5
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2024-10-08
卷号121期号:41页码:11
关键词GPCR somatostatin receptors ligand selectivity neuroendocrine tumor |cryo-EM
ISSN号0027-8424
DOI10.1073/pnas.2400298121
英文摘要Somatostatin receptors (SSTRs) exert critical biological functions such as negatively regulating hormone release and cell proliferation, making them popular targets for developing therapeutics to treat endocrine disorders, especially neuroendocrine tumors. Although several panagonists mimicking the endogenous ligand somatostatin are available, the development of more effective and safer somatostatinergic therapies is limited due to a lack of molecular understanding of the ligand recognition and regulation of divergent SSTR subtypes. Here, we report four cryoelectron microscopy structures of Gi-coupled SSTR1 and SSTR3 activated by distinct agonists, including the FDA- approved panagonist pasireotide as well as their selective small molecule agonists L- 797591 and L- 796778. Our structures reveal a conserved recognition pattern of pasireotide in SSTRs attributed to the binding with a conserved extended binding pocket, distinct from SST14, octreotide, and lanreotide. Together with mutagenesis analyses, our structures further reveal the dynamic feature of ligand binding pockets in SSTR1 and SSTR3 to accommodate divergent agonists, the key determinants of ligand selectivity lying across the orthosteric pocket of different SSTR subtypes, as well as the molecular mechanism underlying diversity and conservation of receptor activation. Our work provides a framework for rational design of subtype- selective SSTR ligands and may facilitate drug development efforts targeting SSTRs with improved therapeutic efficacy and reduced side effects.
WOS关键词GROWTH-HORMONE ; PASIREOTIDE ; OCTREOTIDE ; PROLACTIN ; ANALOGS
资助项目Key Program of National Natural Science Foundation of China[82030085] ; National Key Research and Development Program of China[2023YFC2506403] ; National Key Research and Development Program of China[2017YFC0908500] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; National Key R&D Program of China[2022YFC2703105] ; Youth Talent Promotion Project of Chinese Association for Science and Technology ; Youth Innovation Promotion Association of Chinese Academy of Sciences[2023298] ; Natural Science Foundation of Shanghai, China[23ZR1475300] ; Lingang Laboratory[23YF1456700] ; Sailing Program of Shanghai Venus Project ; Special Research Assistant Project of Chinese Academy of Sciences ; Innovative Research Team of Highlevel Local Universities in Shanghai[SHSMU-ZLCX20212300] ; Innovative Research Team of Highlevel Local Universities in Shanghai[SSMU-ZLCX20180500] ; Shanghai Clinical Research Center for Oral Diseases[19MC1910600] ; Shanghai Municipal Key Clinical Specialty[shslczdzk01601] ; Shanghai's Top Priority Research Center[2022ZZ01017] ; [LG-GG-202204-01]
WOS研究方向Science & Technology - Other Topics
WOS记录号WOS:001352306200005
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/314385]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Zhuang, Youwen; Sun, Shuyang
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 9, Dept Oral & Maxillofacial Head & Neck Oncol, Shanghai 200011, Peoples R China
2.Natl Ctr Stomatol, Natl Clin Res Ctr Oral Dis, Shanghai 200011, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Adv Electron Microscope Ctr, Shanghai 201203, Peoples R China
4.Shanghai Jiao Tong Univ, Shanghai Res Inst Stomatol, Coll Stomatol, Shanghai Key Lab Stomatol, Shanghai 200011, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Shanghai Jiao Tong Univ, Med Bioinformat Ctr, Sch Med, Shanghai 200025, Peoples R China
8.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yujue,Xu, Youwei,Wang, Yue,et al. Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2024,121(41):11.
APA Wang, Yujue.,Xu, Youwei.,Wang, Yue.,Zhang, Jie.,Chen, Lan.,...&Sun, Shuyang.(2024).Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,121(41),11.
MLA Wang, Yujue,et al."Selective ligand recognition and activation of somatostatin receptors SSTR1 and SSTR3".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 121.41(2024):11.

入库方式： OAI收割

来源：上海药物研究所

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