Molecular basis of enhanced GLP-1 signaling mediated by GLP-1(9-36) in conjunction with LSN3318839  

作　　者：Jie Li Guanyi Li Yiting Mai Xiao Liu Dehua Yang Qingtong Zhou Ming-Wei Wang 

机构地区：[1]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [2]School of Pharmaceutical Sciences,Shanghai Jiao Tong University,Shanghai 200240,China [3]Research Center for Deepsea Bioresources,Sanya 572025,China [4]The National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [5]Translational Research Center for Structural Biology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [6]Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education,School of Pharmacy,Hainan Medical University,Haikou 570228,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第11期5069-5073,共5页药学学报（英文版）

基　　金：National Natural Science Foundation of China 82273961(Ming-Wei Wang),82073904(Ming-Wei Wang)and 81872915(Ming-Wei Wang);STI2030-Major Project(China)2021ZD0203400(Qingtong Zhou);Hainan Provincial Major Science and Technology Project(China)ZDKJ2021028(Dehua Yang and Qingtong Zhou).

摘　　要：To the Editor:Glucagon-like peptide-1(GLP-1)receptor(GLP-1R)is a well-established drug target for type 2 diabetes and obesity.It is activated by the endogenous hormone GLP-1(7-36)NH_(2)[GLP-1(7-36)hereafter]to maintain glucose homeostasis1.GLP-1(7-36),produced through the proteolytic processing of proglucagon and released by L cells in the small intestine and colon,is rapidly degraded by dipeptidyl peptidase 4 with a half-life of approximately 2 min.The resulting metabolite,GLP-1(9-36)NH_(2)[GLP-1(9-36)hereafter],lacks the N-terminal dipeptide His7 and Ala8(Supporting Information Fig.S1A)2 and constitutes approximately 60%of circulating GLP-13.Compared to GLP-1(7-36),GLP-1(9-36)is a low potency and weak partial agonist of GLP-1R(Fig.1A)4.It was initially believed to be biologically inactive.However,GLP-1(9-36)has been implicated in hepatic glucose production5,glycemic control6 and glucagonostatic actions7,8.Its cardiovascular9,10 and neuroprotective benefits11,12 were also reported.

关 键 词：GLP-1(9-36) Cryo-electron microscopy METABOLITE Allosteric modulation 

分 类 号：R587.1[医药卫生—内分泌]