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Structural insights into ligand recognition and selectivity of somatostatin receptors

Wenli Zhao1,2,† , Shuo Han1,3,† , Na Qiu1,2,† , Wenbo Feng4,† , Mengjie Lu1,2,† , Wenru Zhang5 , Mu Wang1,6 , Qingtong Zhou4 , Shutian Chen1,2 , Wei Xu1,2 , Juan Du1,3 , Xiaojing Chu1 , Cuiying Yi1 , Antao Dai7 , Liaoyuan Hu8 , Michelle Y. Shen8 , Yaping Sun8 , Qing Zhang8 , Yingli Ma8 , Wenge Zhong8,9 , Dehua Yang1,2,7,* , Ming-Wei Wang1,2,4,6,7,* , Beili Wu1,2,3,6,* , Qiang Zhao1,2,5,10,*

1State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
2University of Chinese Academy of Sciences, Beijing, China
3School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang, China
4Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China
5School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
6School of Life Science and Technology, ShanghaiTech University, Shanghai, China
7The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
8Amgen Asia R&D Center, Shanghai, China
9Regor Therapeutics, Shanghai, China
10Zhongshan Institute of Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, China
These authors contributed equally: Wenli Zhao, Shuo Han, Na Qiu, Wenbo Feng, Mengjie Lu
* Correspondence: Dehua Yang( Wang( Wu( Zhao(

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.


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