Tuning insulin receptor signaling using de novo-designed agonists
Open accessPublished version of a preprint
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.
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- Authors
- 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.
- Affiliations
- University of Washington (US)
- Columbia University Irving Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- Columbia University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wang, Xinru
- Choi, Eunhee
- Bai, Xiao-chen
- Baker, David
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-11
- Volume
- 85
- Issue
- 21
- Pages
- 4064-4081.e9
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4415226693
- Cited by
- 24
- References
- 11
- Citations by year
- 2026: 19 · 2025: 5
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK132361)
- National Institute of General Medical Sciences (R35GM142937, R35GM156386)
- Cancer Prevention and Research Institute of Texas (RP170644)
- Irma T Hirschl Trust
- Howard Hughes Medical Institute
- Audacious Project
- Welch Foundation (I-1944)
- Feldstein Medical Foundation
- National Institutes of Health
- Open Philanthropy Project
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- insulin receptor, de novo protein design, receptor conformational change, MAPK signaling, Akt signaling, receptor autophosphorylation, receptor trafficking, tumor cell proliferation, blood glucose reduction, metabolic disorders, receptor dimerization
- MeSH terms
- Animals, Humans, Hypoglycemic Agents, Insulin, Phosphorylation, Protein Conformation, Receptor, Insulin, Signal Transduction, Antigens, CD, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice, HEK293 Cells
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