Tuning insulin receptor signaling using de novo-designed agonists

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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Publication Details

Journal
Molecular Cell
Published
2025-10-15
DOI
https://doi.org/10.1016/j.molcel.2025.09.020
Citations
8
Primary Topic
Receptor Mechanisms and Signaling
Type
article
Field-Weighted Citation Impact
6.45
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article

Tuning insulin receptor signaling using de novo-designed agonists

Brian Coventry, Preetham Venkatesh, Xiao‐chen Bai, Domenico Accili et al.
8 citations
Molecular Cell
Receptor Mechanisms and Signaling
6.45
article

Tuning insulin receptor signaling using de novo-designed agonists

Brian Coventry, Preetham Venkatesh, Xiao‐chen Bai, Domenico Accili, Kaiyong Cai, Eunhee Choi, Catherine Hall, Michael Gao, David A. Baker, Ya-Cheng Liao, Weidong An, Albert Hung, Jie Li, Michelle Ng, Xinru Wang, David Lee, Stacey Gerben, Sarah Cardoso, Rishabh Chowhan, Mara Hon
article en
8 citations

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.

Molecular CellVol. 85(21)
University of Washington (US), University of Washington Medical Center (US), Southwestern Medical Center (US), University of Washington Applied Physics Laboratory (US), Columbia University (US), The University of Texas Southwestern Medical Center (US)
Openalex Percentile: Top 3%
Receptor Mechanisms and Signaling
6.45
DOIOpen Access PDFOpenAlex
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