ADVANCE ONLINE PUBLICATION
Structures of the endogenous peptide- and selective non-peptide agonist-bound SSTR2 signaling complexes
Li-Nan Chen1,2,3,† , Wei-Wei Wang4,† , Ying-Jun Dong1,† , Dan-Dan Shen1 , Jia Guo1 , Xuefei Yu5 , Jiao Qin1 , Su-Yu Ji1 , Huibing Zhang1 , Qingya Shen1 , Qiaojun He6 , Bo Yang6 , Yan Zhang1,3,4,7,8 , Qinglin Li5,* , Chunyou Mao2,3,*1Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China
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. Pharmacologically, somatostatin receptors, especially SSTR2, are the primary drug targets for the treatment of pituitary adenomas and neuroendocrine tumors.1,2,3 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,4,5,6,7 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–Gi1 complexes 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.