8QUP

G-CSFR inhibitor Bop1

Summary for 8QUP

• Entry DOI: 10.2210/pdb8qup/pdb
• Descriptor: Bop1 (2 entities in total)
• Functional Keywords: granulocyte-colony stimulating factor, granulopoiesis, de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 13730.91

Authors

Ulrich, T.,ElGamacy, M.,Hartmann, M.D. (deposition date: 2023-10-16, release date: 2024-10-23, Last modification date: 2025-12-10)

Primary citation

Ullrich, T.,Klimenkova, O.,Pollmann, C.,Lasram, A.,Hatskovska, V.,Maksymenko, K.,Milijas-Jotic, M.,Schenk, L.,Lengerke, C.,Hartmann, M.D.,Piehler, J.,Skokowa, J.,ElGamacy, M.
A strategy to design protein-based antagonists against type I cytokine receptors.
Plos Biol., 22:e3002883-e3002883, 2024

PubMed Abstract: 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, the resulting designs can be used for inhibiting or homing to G-CSFR-expressing cells. Our results also demonstrate that similarly designed cytokine mimics can be used to derive antagonists to tackle other type I cytokine receptors.

PubMed: 39591631
DOI: 10.1371/journal.pbio.3002883

Experimental method

X-RAY DIFFRACTION (1.3 Å)