8GUY

human insulin receptor bound with two insulin molecules

8GUY の概要

• エントリーDOI: 10.2210/pdb8guy/pdb
• EMDBエントリー: 34281
• 分子名称: Isoform Short of Insulin receptor, Insulin A chain, Insulin, isoform 2 (3 entities in total)
• 機能のキーワード: receptor-ligand complex, structural 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: 217735.05

構造登録者

Kim, J.,Yunn, N.,Ryu, S.,Cho, Y. (登録日: 2022-09-14, 公開日: 2022-11-09, 最終更新日: 2024-11-20)

主引用文献

Kim, J.,Yunn, N.O.,Park, M.,Kim, J.,Park, S.,Kim, Y.,Noh, J.,Ryu, S.H.,Cho, Y.
Functional selectivity of insulin receptor revealed by aptamer-trapped receptor structures.
Nat Commun, 13:6500-6500, 2022

PubMed Abstract: Activation of insulin receptor (IR) initiates a cascade of conformational changes and autophosphorylation events. Herein, we determined three structures of IR trapped by aptamers using cryo-electron microscopy. The A62 agonist aptamer selectively activates metabolic signaling. In the absence of insulin, the two A62 aptamer agonists of IR adopt an insulin-accessible arrowhead conformation by mimicking site-1/site-2' insulin coordination. Insulin binding at one site triggers conformational changes in one protomer, but this movement is blocked in the other protomer by A62 at the opposite site. A62 binding captures two unique conformations of IR with a similar stalk arrangement, which underlie Tyr1150 mono-phosphorylation (m-pY1150) and selective activation for metabolic signaling. The A43 aptamer, a positive allosteric modulator, binds at the opposite side of the insulin-binding module, and stabilizes the single insulin-bound IR structure that brings two FnIII-3 regions into closer proximity for full activation. Our results suggest that spatial proximity of the two FnIII-3 ends is important for m-pY1150, but multi-phosphorylation of IR requires additional conformational rearrangement of intracellular domains mediated by coordination between extracellular and transmembrane domains.

PubMed: 36310231
DOI: 10.1038/s41467-022-34292-8

実験手法

ELECTRON MICROSCOPY (4.18 Å)