biostudies-literatureUllrich TDeutsche ForschungsgemeinschaftJosé Carreras Leukämie-StiftungM. Schickedanz KinderkrebsstiftungMax-Planck-Gesellschafte3002883https://www.ebi.ac.uk/biostudies/studies/S-EPMC11596305biostudies-literatureUnknown22(11)Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle the granulocyte-colony stimulating factor receptor (G-CSFR), a mediator of different types of leukemia and autoinflammatory diseases. By modifying designed G-CSFR binders, we engineered hyper-stable proteins that function as nanomolar signaling antagonists. X-ray crystallography showed atomic-level agreement with the experimental structure of an exemplary design. Furthermore, the most potent design blocks G-CSFR in acute myeloid leukemia cells and primary human hematopoietic stem cells. Thus, thePLoS biologyA strategy to design protein-based antagonists against type I cytokine receptors.PMC11596305500215849DJCLS 10 R/2024PI 405/15Skokowa JLasram APiehler JMilijas-Jotic MUllrich THatskovska VSchenk LElGamacy MKlimenkova OPollmann CMaksymenko KHartmann MDLengerke CfalseA strategy to design protein-based antagonists against type I cytokine receptors.Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle the granulocyte-colony stimulating factor receptor (G-CSFR), a mediator of different types of leukemia and autoinflammatory diseases. By modifying designed G-CSFR binders, we engineered hyper-stable proteins that function as nanomolar signaling antagonists. X-ray crystallography showed atomic-level agreement with the experimental structure of an exemplary design. Furthermore, the most potent design blocks G-CSFR in acute myeloid leukemia cells and primary human hematopoietic stem cells. Thus, the2024-01-01T00:00:00Z2024 Nov2026-06-01T06:43:44.2Z2025-04-04T00:45:20.503ZS-EPMC115963053959163110.1371/journal.pbio.3002883