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ORIGINAL ARTICLES

Structural insights into ligand recognition and selectivity of somatostatin receptors

Wenli Zhao^1,2,† , Shuo Han^1,3,† , Na Qiu^1,2,† , Wenbo Feng^4,† , Mengjie Lu^1,2,† , Wenru Zhang⁵ , Mu Wang^1,6 , Qingtong Zhou⁴ , Shutian Chen^1,2 , Wei Xu^1,2 , Juan Du^1,3 , Xiaojing Chu¹ , Cuiying Yi¹ , Antao Dai⁷ , Liaoyuan Hu⁸ , Michelle Y. Shen⁸ , Yaping Sun⁸ , Qing Zhang⁸ , Yingli Ma⁸ , Wenge Zhong^8,9 , Dehua Yang^1,2,7,* , Ming-Wei Wang^1,2,4,6,7,* , Beili Wu^1,2,3,6,* , Qiang Zhao^1,2,5,10,*

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(dhyang@simm.ac.cn)Ming-Wei Wang(mwwang@simm.ac.cn)Beili Wu(beiliwu@simm.ac.cn)Qiang Zhao(zhaoq@simm.ac.cn)

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.

https://doi.org/10.1038/s41422-022-00679-x

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