7TYM

Cryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry

7TYM の概要

• エントリーDOI: 10.2210/pdb7tym/pdb
• EMDBエントリー: 26181 26183 26185
• 分子名称: Insulin receptor-related protein (1 entity in total)
• 機能のキーワード: receptor tyrosine kinase, insulin receptor family, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 287759.09

構造登録者

Wang, L.W.,Hall, C.,Li, J.,Choi, E.,Bai, X.C. (登録日: 2022-02-13, 公開日: 2023-02-15, 最終更新日: 2024-10-30)

主引用文献

Wang, L.,Hall, C.,Li, J.,Choi, E.,Bai, X.C.
Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor.
Nat.Struct.Mol.Biol., 30:661-669, 2023

PubMed Abstract: The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state and promotes a scissor-like rotation between two protomers, leading to a T-shaped active conformation. Together, our study reveals an unprecedented alkaline pH-dependent activation mechanism of IRR, opening up opportunities to understand the structure-function relationship of this important receptor.

PubMed: 37055497
DOI: 10.1038/s41594-023-00974-0

実験手法

ELECTRON MICROSCOPY (3.4 Å)