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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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A strategy to design protein-based antagonists against type I cytokine receptors

Timo Ullrich1, Olga Klimenkova2, Christoph Pollmann3

  • 1Max Planck Institute for Biology, Department of Protein Evolution, Tübingen, Germany.

Plos Biology
|November 26, 2024
PubMed

Insights

Scientists engineered novel protein blockers to inhibit granulocyte-colony stimulating factor receptor (G-CSFR) signaling. These hyper-stable G-CSFR antagonists show promise for treating leukemia and autoinflammatory diseases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Protein Engineering

Background:

  • Dysregulated cytokine signaling drives cancer, autoimmune, and hematopoietic disorders.
  • The granulocyte-colony stimulating factor receptor (G-CSFR) is implicated in leukemia and autoinflammatory diseases.

Purpose of the Study:

  • To engineer hyper-stable protein blockers targeting the G-CSFR.
  • To develop nanomolar signaling antagonists for G-CSFR.

Main Methods:

  • Protein design and engineering of G-CSFR binders.
  • X-ray crystallography for structural validation.
  • Functional assays in leukemia cells and hematopoietic stem cells.

Main Results:

  • Engineered hyper-stable proteins acting as nanomolar G-CSFR signaling antagonists.
  • X-ray crystallography confirmed atomic-level design accuracy.
  • Potent G-CSFR blockade observed in acute myeloid leukemia cells and human hematopoietic stem cells.

Conclusions:

  • Designed G-CSFR blockers can inhibit G-CSFR signaling and target G-CSFR-expressing cells.
  • This protein design approach can be extended to develop antagonists for other type I cytokine receptors.

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