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Gutmann, T. ; Schäfer, I.B.* ; Poojari, C.* ; Brankatschk, B. ; Vattulainen, I.* ; Strauss, M.* ; Coskun, Ü.

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

J. Cell Biol. 219:e201907210 (2020)
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Real-space Refinement; Particle Mesh Ewald; Negative Cooperativity; Quaternary Structure; Linked Glycans; Egf Receptor; Binding; Protein; Dynamics; Domain
Language english
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0021-9525
e-ISSN 1540-8140
Journal Journal of Cell Biology, The
Quellenangaben Volume: 219, Issue: 1, Pages: , Article Number: e201907210 Supplement: ,
Publisher Rockefeller University Press
Publishing Place 950 Third Ave, 2nd Flr, New York, Ny 10022 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502600-002
DOI 10.1083/jcb.201907210
WOS ID WOS:000525668800023
Scopus ID 85076326687
PubMed ID 31727777
Erfassungsdatum 2019-11-26
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