生物
胰岛素受体
细胞内
受体
胰岛素
激酶
蛋白激酶A
细胞外
信号转导
蛋白激酶结构域
MAPK/ERK通路
生物化学
细胞生物学
细胞生长
IRS2
构象变化
蛋白激酶B
原癌基因蛋白质c-akt
变构调节
磷酸化
体内
兴奋剂
胰岛素受体底物
细胞代谢
细胞表面受体
细胞
细胞信号
新陈代谢
血浆蛋白结合
β肾上腺素能受体激酶
酶
作者
Xinru Wang,Sarah Cardoso,Kaiyong Cai,Preetham Venkatesh,Albert Hung,Michelle Ng,Catherine Hall,Brian Coventry,David Lee,Rishabh Chowhan,Stacey Gerben,Jie Li,Weidong An,Mara Hon,Michael Gao,Ya-Cheng Liao,Domenico Accili,Eunhee Choi,Xiao‐chen Bai,David Baker
出处
期刊:Molecular Cell
[Elsevier BV]
日期:2025-10-15
卷期号:85 (21): 4064-4081.e9
被引量:8
标识
DOI:10.1016/j.molcel.2025.09.020
摘要
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.
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