Structural insights into somatostatin receptor 5 bound with cyclic peptides  

作　　者：Ying-ge Li Xian-yu Meng Xiru Yang Sheng-long Ling Pan Shi Chang-lin Tian Fan Yang 

机构地区：[1]The First Affiliated Hospital of USTC,School of Life Sciences,Division of Life Sciences and Medicine,Joint Center for Biological Analytical Chemistry,Anhui Engineering Laboratory of Peptide Drug,Anhui Laboratory of Advanced Photonic Science and Technology,University of Science and Technology of China,Hefei,230026,China [2]The Anhui Provincial Key Laboratory of High Magnetic Resonance Image,High Magnetic Field Laboratory,Chinese Academy of Sciences,Hefei,230031,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2432-2440,共9页中国药理学报（英文版）

基　　金：supported by“USTC Research Funds of the Double First-Class Initiative”(YD9990002027 to FY,YD9100002021 to PS);the National Natural Science Foundation of China(22207100 to FY,22277114,31971152 to PS,21825703 to CLT,22307113 to SLL);the National Key Research&Development Project,Ministry of Science and Technology the China(2022YFC3400500 to CLT);Postdoctoral Science Foundation(2022M713054 to FY);the Strategic Priority Research Program of Chinese Academy of Sciences(XDB37000000 to CLT);Anhui Provincial Natural Science Foundation(2108085J16 to PS);And the National Key R&D Program of China(2021YFA1200104 to SLL);supported by“the Fundamental Research Funds for the Central Universities”.

摘　　要：Somatostatin receptor 5(SSTR5)is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing’s disease.Two cyclic SST analog peptides(pasireotide and octreotide)both can activate SSTR5 and SSTR2.Pasireotide is preferential binding to SSTR5 than octreotide,while octreotide is biased to SSTR2 than SSTR5.The lack of selectivity of both pasireotide and octreotide causes side effects,such as hyperglycemia,gastrointestinal disturbance,and abnormal glucose homeostasis.However,little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5,limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5.Here,we report two cryo-electron microscopy(cryo-EM)structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09Åand 3.24Å,respectively.In combination with structural analysis and functional experiments,our results reveal the molecular mechanisms of ligand recognition and receptor activation.We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/DTrp of pasireotide and SSTR5.Moreover,we find that the Q^(2.63),N^(6.55),F^(7.35)and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2.Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes.

关 键 词：G protein-coupled receptors Somatostatin receptor 5 PASIREOTIDE OCTREOTIDE CRYO-EM 

分 类 号：O62[理学—有机化学]