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

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Gutmann , T , Schäfer , I B , Poojari , C , Brankatschk , B , Vattulainen , I T , Strauss , M & Coskun , Ü 2020 , ' Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain ' , Journal of Cell Biology , vol. 219 , no. 1 , 201907210 . https://doi.org/10.1083/jcb.201907210

Title: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain
Author: Gutmann, Theresia; Schäfer, Ingmar B.; Poojari, Chetan; Brankatschk, Beate; Vattulainen, Ilpo Tapio; Strauss, Mike; Coskun, Ünal
Contributor: University of Helsinki, Department of Physics
University of Helsinki, Department of Physics
Date: 2020-01-06
Language: eng
Number of pages: 16
Belongs to series: Journal of Cell Biology
ISSN: 0021-9525
URI: http://hdl.handle.net/10138/310454
Abstract: 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.
Subject: 1182 Biochemistry, cell and molecular biology
114 Physical sciences
Biological Physics
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