Dear Editor, Somatostatin,also known as growth hormone-inhibiting hormone,is an important peptide hormone that mediates predominantly neuroendocrine inhibitory effects in the exocrine and endocrine systems.1,2 Besides,it can also exert potent regulatory effects on cell proliferation and angiogenesis.3 In human,somatostatin exerts its physiological functions through activating five somatostatin receptors(SSTRs),which are class A Gi/o protein-coupled receptors.Pharmaco-logically,somatostatin receptors,especially SSTR2,are the primary drug targets for the treatment of pituitary adenomas and neuroendo-crine tumors.1-3 To date,three somatostatin analogs have been approved for clinical use and two of them(lanreotide and octreotide)are SSTR2-selective drugs.3 In addition to peptidic agonists,extensive efforts have also been made to design selective small-molecule agonists,4-7 which will facilitate the development of orally active chemotherapeutic agents.Yet,the limited structural information of SSTRs has hindered our understanding of the ligand recognition mode and the structure-guided drug discovery.Here,we present two cryo-electron microscopy(cryo-EM)structures of SSTR2-Gii com-plexes activated by the endogenous peptide(SS-14)and a selective non-peptide agonist(L-054,264).Combined with functional analysis,our results reveal the structural basis of ligand-binding mode and non-peptide agonist subtype-selectivity of SSTR2.

Li-Nan Chen;Wei-Wei Wang;Ying-Jun Dong;Dan-Dan Shen;Jia Guo;Xuefei Yu;Jiao Qin;Su-Yu Ji;Huibing Zhang;Qingya Shen;Qiaojun He;Bo Yang;Yan Zhang;Qinglin Li;Chunyou Mao

Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University,School of Medicine,Hangzhou,Zhejiang,China;Department of General Surgery,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China;Center for Structural Pharmacology and Therapeutics Development,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China;Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,Zhejiang,China;The Cancer Hospital of the University of Chinese Academy of Sciences(Zhejiang Cancer Hospital),Hangzhou,Zhejiang,China;Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,Zhejiang,China;MOE Frontier Science Center for Brain Research and Brain-Machine Integration,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China;Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases,Hangzhou,Zhejiang,China

细胞研究（英文版）

[1]Li-Nan Chen;Wei-Wei Wang;Ying-Jun Dong;Dan-Dan Shen;Jia Guo;Xuefei Yu;Jiao Qin;Su-Yu Ji;Huibing Zhang;Qingya Shen;Qiaojun He;Bo Yang;Yan Zhang;Qinglin Li;Chunyou Mao-.Structures of the endogenous peptide-and selective non-peptide agonist-bound SSTR2 signaling complexes)[J].细胞研究（英文版）,2022(08):785-788

Somatostatin,SSTRs,Pharmaco,neuroendo,crine,lanreotide,octreotide,peptidic,Gii

Structures,endogenous,peptide,selective,bound,SSTR2,signaling,complexes,Dear,Editor,also,known,growth,hormone,inhibiting,important,that,mediates,predominantly,neuroendocrine,inhibitory,effects,exocrine,systems,Besides,can,potent,regulatory,cell,proliferation,angiogenesis,In,human,somatostatin,exerts,its,physiological,functions,through,activating,five,receptors,which,are,class,protein,coupled,logically,especially,primary,targets,treatment,pituitary,adenomas,tumors,To,date,three,analogs,have,been,approved,clinical,use,two,them,drugs,addition,agonists,extensive,efforts,made,design,small,molecule,will,facilitate,development,orally,active,chemotherapeutic,agents,Yet,limited,structural,information,has,hindered,our,understanding,ligand,recognition,mode,guided,discovery,Here,we,present,cryo,electron,microscopy,EM,structures,activated,by,Combined,functional,analysis,results,reveal,basis,binding,subtype,selectivity

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