Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues

doi:10.1038/s41421-022-00405-2

	Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues
	Bo, Qing 2,3; Yang, Fan 2,3; Li, Yingge 2,3; Meng, Xianyu 2,3; Zhang, Huanhuan 2,3; Zhou, Yingxin 2,3; Ling, Shenglong 2,3; Sun, Demeng 2,3; Lv, Pei 2,3; Liu, Lei 4
刊名	CELL DISCOVERY
	2022-05-20
卷号	8
DOI	10.1038/s41421-022-00405-2
通讯作者	Liu, Lei(lliu@mail.tsinghua.edu.cn) ; Shi, Pan(shipan@ustc.edu.cn) ; Tian, Changlin(cltian@ustc.edu.cn)
英文摘要	The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 angstrom, 2.97 angstrom, and 2.87 angstrom, respectively. Structural and functional analysis revealed that interactions between beta-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q102(2.63), N276(6.55), and F294(7.35) could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.
资助项目	National Natural Science Foundation of China[21825703] ; National Natural Science Foundation of China[31971152] ; National Natural Science Foundation of China[22137005] ; National Key R&D Program of China[2016YFA0400903] ; National Key R&D Program of China[2017YFA0505400] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB37000000] ; Anhui Provincial Natural Science Foundation[2108085J16] ; Collaborative Innovation Program of Hefei Science Center, Chinese Academy of Sciences[2021HSC-CIP011] ; China National Postdoctoral Program for Innovative Talents[BH2340000159]
WOS关键词	NEUROENDOCRINE TUMORS ; IN-VITRO ; OCTAPEPTIDE ANALOG ; CRYO-EM ; OCTREOTIDE ; EXPRESSION ; GROWTH ; VIVO ; SELECTIVITY ; INHIBITION
WOS研究方向	Cell Biology
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000798186300001
资助机构	National Natural Science Foundation of China ; National Key R&D Program of China ; Strategic Priority Research Program of Chinese Academy of Sciences ; Anhui Provincial Natural Science Foundation ; Collaborative Innovation Program of Hefei Science Center, Chinese Academy of Sciences ; China National Postdoctoral Program for Innovative Talents
内容类型	期刊论文
源URL	[http://ir.hfcas.ac.cn:8080/handle/334002/130965]
专题	中国科学院合肥物质科学研究院
通讯作者	Liu, Lei; Shi, Pan; Tian, Changlin
作者单位	1.Chinese Acad Sci, High Magnet Field Lab, Hefei, Anhui, Peoples R China 2.Univ Sci & Technol China, Affiliated Hosp USTC 1, Anhui Engn Lab Peptide Drug,Anhui Lab Adv Photon, Sch Life Sci,Div Life Sci & Med,Joint Ctr Biol An, Hefei, Anhui, Peoples R China 3.Univ Sci & Technol China, Dept Chem, Hefei, Anhui, Peoples R China 4.Tsinghua Univ, Tsinghua Peking Joint Ctr Life Sci, Minist Educ, Key Lab Bioorgan Phosphorus Chem & Chem Biol, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Bo, Qing,Yang, Fan,Li, Yingge,et al. Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues[J]. CELL DISCOVERY,2022,8.
APA	Bo, Qing.,Yang, Fan.,Li, Yingge.,Meng, Xianyu.,Zhang, Huanhuan.,...&Tian, Changlin.(2022).Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues.CELL DISCOVERY,8.
MLA	Bo, Qing,et al."Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues".CELL DISCOVERY 8(2022).