Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain

被引:80
作者
Gutmann, Theresia [1 ,2 ,3 ]
Schaefer, Ingmar B. [4 ]
Poojari, Chetan [5 ]
Brankatschk, Beate [1 ,2 ,3 ]
Vattulainen, Ilpo [5 ,6 ]
Strauss, Mike [7 ]
Coskun, Uenal [1 ,2 ,3 ]
机构
[1] Univ Hosp, Paul Langerhans Inst Dresden, Helmholtz Zentrum Munich, Dresden, Germany
[2] Tech Univ Dresden, Fac Med Carl Gustav Carus, Dresden, Germany
[3] German Ctr Diabet Res, Neuherberg, Germany
[4] Max Planck Inst Biochem, Dept Struct Cell Biol, Munich, Germany
[5] Univ Helsinki, Dept Phys, Helsinki, Finland
[6] Tampere Univ, Computat Phys Lab, Tampere, Finland
[7] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ, Canada
基金
欧洲研究理事会; 芬兰科学院;
关键词
REAL-SPACE REFINEMENT; PARTICLE MESH EWALD; NEGATIVE COOPERATIVITY; QUATERNARY STRUCTURE; LINKED GLYCANS; EGF RECEPTOR; BINDING; PROTEIN; DYNAMICS; DOMAIN;
D O I
10.1083/jcb.201907210
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Glucose homeostasis and growth essentially depend on the hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have resolved only site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we present the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis for a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.
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页数:16
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