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

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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.
Originalspråkengelska
Artikelnummer201907210
TidskriftJournal of Cell Biology
Volym219
Utgåva1
Antal sidor16
ISSN0021-9525
DOI
StatusPublicerad - 6 jan 2020
MoE-publikationstypA1 Tidskriftsartikel-refererad

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