Structural basis for the conformational changes of insulin receptor induced by three different hormone ligandsOA
The insulin receptor(IR)is central to the regulation of glucose and lipid metabolism.Although insulin is its primary ligand,insulin-like growth factorsⅠandⅡ(IGF-Ⅰand IGF-Ⅱ)also engage IR,albeit with reduced affinity.The structural basis of cooperative ligand binding,however,has remained poorly understood.Here,we report cryo-Electron Microscopy(cryo-EM)structures of IR in complex with insulin,IGF-Ⅰ,and IGF-Ⅱ,revealing that all three ligands engage the receptor at overlapping binding sites and can induce a conserved T-shaped quaternary assembly involving four ligand molecules at site 1/1'and site 2/2'.Despite this shared overall architecture,distinct ligandspecific conformational changes are observed.Notably,IGF-Ⅰand IGF-Ⅱadopt different binding sequence at site 1 and site 2 compared to insulin,suggesting unique interaction dynamics.These structural insights highlight divergent mechanisms of ligand recognition and cooperative binding,providing a deeper understanding of hormoneinduced conformational modulation of the IR.
Xi Zhang;Ting Zhang;Cang Wu;Yuanzhu Gao;Shuo Zhang;Zhenglin Li;Linshan Zhong;Chenyu Xia;Liuqing Yang;Fengquan Dong;Qing Shu;Yang Fu;Renhong Yan
Department of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen 518055,ChinaCryo-EM Centre,Southern University of Science and Technology,Shenzhen 518055,ChinaSchool of Life Sciences,Zhengzhou University,Zhengzhou 450001,ChinaDepartment of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biology,School of Life Sciences,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,ChinaCardiovascular Medicine,Shenzhen University General Hospital,Shenzhen 518055,ChinaDepartment of Gastroenterology,The First Affiliated Hospital of Shenzhen University,Shenzhen People's Second Hospital,Shenzhen 518000,ChinaDepartment of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,ChinaDepartment of Biochemistry,SUSTech Homeostatic Medicine Institute,School of Medicine,Key University Laboratory of Metabolism and Health of Guangdong,Institute for Biological Electron Microscopy,Southern University of Science and Technology,Shenzhen 518055,China
医药卫生
insulin receptorIGF-ⅠIGF-Ⅱcryo-electron microscopy
《Acta Biochimica et Biophysica Sinica》 2026 (6)
P.1273-1280,8
supported by the grants from the National Natural Science Foundation of China(No.32422039 to R.Y.)the Shenzhen Science and Technology Program(No.RCYX20231211090342048 to R.Y.)the Shenzhen Medical Research Fund(Nos.A2303046 and B2402043 to R.Y.)the Major Talent Recruitment Program of Guangdong Province(No.2021QNO2Y167 to R.Y.)the Medical Scientific Research Foundation of Guangdong Province of China(No.A2021333 to F.Q.D.)Shenzhen Science and Technology Innovation Commission Project(No.JCYJ20190808120613189 to F.Q.D.)Shenzhen science and technology research and development fund pr0ject(No.KCXFZ20201221173208023-1039027 to Q.S.)the Shenzhen Pea-cock Team Project(No.KQTD20200909113758004 to Y.F.)And Special thanks to the support of Taidu Biotech(Suzhou)Co.,Ltd.in protein purification equipments.
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