9DNN

Insulin receptor in complex with both insulin and de novo designed site-2 binder "S2B".

9DNN の概要

• エントリーDOI: 10.2210/pdb9dnn/pdb
• EMDBエントリー: 47043
• 分子名称: Insulin receptor, Insulin, Designed site-2 binder S2B (3 entities in total)
• 機能のキーワード: insulin receptor, insulin, designed binder, signaling protein
• 由来する生物種: Mus musculus (house mouse); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 350666.22

構造登録者

Bai, X.C. (登録日: 2024-09-17, 公開日: 2025-10-01, 最終更新日: 2025-11-19)

主引用文献

Wang, X.,Cardoso, S.,Cai, K.,Venkatesh, P.,Hung, A.,Ng, M.,Hall, C.,Coventry, B.,Lee, D.S.,Chowhan, R.,Gerben, S.,Li, J.,An, W.,Hon, M.,Gao, M.,Liao, Y.C.,Accili, D.,Choi, E.,Bai, X.C.,Baker, D.
Tuning insulin receptor signaling using de novo-designed agonists.
Mol.Cell, 85:4064-, 2025

PubMed Abstract: Insulin binding induces conformational changes in the insulin receptor (IR) that activate the intracellular kinase domain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulating metabolism and proliferation. We reasoned that designed agonists inducing different IR conformational changes might induce different downstream responses. We used de novo protein design to generate binders for individual IR extracellular domains and fused them in different orientations with different conformational flexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPK activation, trafficking, and proliferation responses. We identified designs more potent than insulin, causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, while largely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes in IR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.

PubMed: 41086805
DOI: 10.1016/j.molcel.2025.09.020

実験手法

ELECTRON MICROSCOPY (6.1 Å)