Somatostatin receptors(SSTRs)play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone,and thus are considered as targets for treating multiple tumors.Despite great progress made in therapeutic development against this diverse receptor family,drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects.Here,we report five structures of SSTR2 and SSTR4 in different states,including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist,respectively,a cryo-electron microscopy(cryo-EM)structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14,as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156,respectively.By comparison of the SSTR structures in different states,molecular mechanisms of agonism and antagonism were illustrated.Together with computational and functional analyses,the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified.Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Wenli Zhao;Shuo Han;Na Qiu;Wenbo Feng;Mengjie Lu;Wenru Zhang;Mu Wang;Qingtong Zhou;Shutian Chen;Wei Xu;Juan Du;Xiaojing Chu;Cuiying Yi;Antao Dai;Liaoyuan Hu;Michelle Y.Shen;Yaping Sun;Qing Zhang;Yingli Ma;Wenge Zhong;Dehua Yang;Ming-Wei Wang;Beili Wu;Qiang Zhao

State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;University of Chinese Academy of Sciences,Beijing,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou,Zhejiang,China;Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai,China;School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,Jiangsu,China;School of Life Science and Technology,ShanghaiTech University,Shanghai,China;The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;Amgen Asia R&D Center,Shanghai,China;Regor Therapeutics,Shanghai,China;Zhongshan Institute of Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,Guangdong,China

细胞研究（英文版）

[1]Wenli Zhao;Shuo Han;Na Qiu;Wenbo Feng;Mengjie Lu;Wenru Zhang;Mu Wang;Qingtong Zhou;Shutian Chen;Wei Xu;Juan Du;Xiaojing Chu;Cuiying Yi;Antao Dai;Liaoyuan Hu;Michelle Y.Shen;Yaping Sun;Qing Zhang;Yingli Ma;Wenge Zhong;Dehua Yang;Ming-Wei Wang;Beili Wu;Qiang Zhao-.Structural insights into ligand recognition and selectivity of somatostatin receptors)[J].细胞研究（英文版）,2022(08):761-772

SSTRs,Gi1,agonism

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