7PG4

Low resolution Cryo-EM structure of the full-length insulin receptor bound to 2 insulin, conf 3

7PG4 の概要

• エントリーDOI: 10.2210/pdb7pg4/pdb
• EMDBエントリー: 13388
• 分子名称: Isoform Short of Insulin receptor, Insulin (3 entities in total)
• 機能のキーワード: insulin, receptor, complex, membrane protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 325030.46

構造登録者

Nielsen, J.A.,Slaaby, R.,Boesen, T.,Hummelshoj, T.,Brandt, J.,Schluckebier, G.,Nissen, P. (登録日: 2021-08-12, 公開日: 2022-02-02, 最終更新日: 2024-11-06)

主引用文献

Nielsen, J.,Brandt, J.,Boesen, T.,Hummelshoj, T.,Slaaby, R.,Schluckebier, G.,Nissen, P.
Structural Investigations of Full-Length Insulin Receptor Dynamics and Signalling.
J.Mol.Biol., 434:167458-167458, 2022

PubMed Abstract: Insulin regulates glucose homeostasis via binding and activation of the insulin receptor dimer at two distinct pairs of binding sites 1 and 2. Here, we present cryo-EM studies of full-length human insulin receptor (hIR) in an active state obtained at non-saturating, physiologically relevant insulin conditions. Insulin binds asymmetrically to the receptor under these conditions, occupying up to three of the four possible binding sites. Deletion analysis of the receptor together with site specific peptides and insulin analogs used in binding studies show that both sites 1 and 2 are required for high insulin affinity. We identify a homotypic interaction of the fibronectin type III domain (FnIII-3) of IR resulting in tight interaction of membrane proximal domains of the active, asymmetric receptor dimer. Our results show how insulin binding at two distinct types of sites disrupts the autoinhibited apo-IR dimer and stabilizes the active dimer. We propose an insulin binding and activation mechanism, which is sequential, exhibits negative cooperativity, and is based on asymmetry at physiological insulin concentrations with one to three insulin molecules activating IR.

PubMed: 35074483
DOI: 10.1016/j.jmb.2022.167458

実験手法

ELECTRON MICROSCOPY (9.1 Å)