Year: 2025
Type: preprint
Abstract: Cytokines signal by bringing receptor subunits together, but the role of receptor geometry in shaping signaling remains unclear because natural ligands enforce fixed assemblies. Here, we present a de novo protein design platform that rigidly scaffolds receptor-binding domains into defined spatial arrangements. Applying this across IL-7, type I and III interferons, IL-10, gp130, β common, and synthetic receptor pairs, we show that by varying geometry, we can bias pSTAT pathway usage and tune functional outcomes. Geometric control allowed us to decouple pSTAT1 from pSTAT5 in IL-7, separate antigen presentation (MHC-I) from checkpoint induction (PD-L1) in type I interferons, and suppress pro-inflammatory IFNγ secretion while retaining anti-inflammatory activity in IL-10. We further created minimal IL-6 and IL-3 agonists and strengthened synthetic receptor pairings inaccessible with present cytokines. These results establish receptor geometry as a central determinant of cytokine activity and provide a platform for programmable immune modulation.
Authors: Marc Expòsit, Mohamad Abedi, Aditya Krishnakumar, Shruti Jain, Ta-Yi Yu, Timothy R. Hercus, Divij Mathew, Sophie Gray-Gaillard, Zhijie Chen, William S. Grubbe, Andrew Favor, Winnie L. Kan, Thomas Schlichthaerle, Wei Chen, Michael W. Parker, Juan L. Mendoza, Angel F. Lopez, E. John Wherry, David Baker
Institutions: University of Washington, South Australia Pathology, University of South Australia, Centre for Cancer Biology, University of Pennsylvania, University of Chicago, The University of Melbourne, Australian Cancer Research Foundation, St Vincents Institute of Medical Research, Howard Hughes Medical Institute, The University of Adelaide
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, Bill and Melinda Gates Foundation, Damon Runyon Cancer Research Foundation, Jane Coffin Childs Memorial Fund for Medical Research, Fred Hutchinson Cancer Research Center, Fundación Rafael del Pino, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, National Institutes of Health, National Cancer Institute
Awards: Design of de novo interleukin mimics for targeted immunotherapy, G4119534169, G5132640529, G5850682332, G6004110409, G7685134749, University of Washington Foundation - to support structure based immunogen design for next-generation vaccines, Novel synthetic receptors with improved antigen specificity and specificity for cancer therapy
OpenAlex ID: W4415174444