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

Theresia Gutmann, Ingmar B. Schäfer, Chetan Poojari, Beate Brankatschk, Ilpo Tapio Vattulainen, Mike Strauss, Ünal Coskun

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
Article number201907210
JournalJournal of Cell Biology
Volume219
Issue number1
Number of pages16
ISSN0021-9525
DOIs
Publication statusPublished - 6 Jan 2020
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • 114 Physical sciences

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