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@ARTICLE{Ullrich:304282,
      author       = {T. Ullrich and C. Pollmann and M. Ritter and J. Haaf and N.
                      Aghaallaei and I. Tesakov and V. Hatskovska and M. El-Riz
                      and K. Maksymenko and S. Kandabarau and M. Klimiankou and C.
                      Lengerke$^*$ and K. Welte and B. Hernandez-Alvarez and P.
                      Müller and A. Lupas and J. Piehler and J. Skokowa and M.
                      ElGamacy},
      title        = {{T}uning of {G}-{CSFR} signaling by de novo designed
                      agonists.},
      journal      = {Molecular therapy},
      volume       = {33},
      number       = {11},
      issn         = {1525-0016},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2025-01822},
      pages        = {5741-5759},
      year         = {2025},
      note         = {2025 Nov 5;33(11):5741-5759},
      abstract     = {Enhancing cytokine-based therapies by systematically tuning
                      how an agonist associates its receptor is emerging as a
                      powerful new concept in drug discovery. Here, we report the
                      design and characterization of agonists that tune the
                      granulocyte-colony stimulating factor receptor (G-CSFR)
                      activity, which is central for the proliferation and
                      granulocytic differentiation of hematopoietic stem cells.
                      Using design agonists, we study the impact of varying the
                      receptor-binding affinity and dimerization geometry on
                      receptor association, downstream signaling, and cellular
                      response. Hence, we achieved agonists with altered signaling
                      specificities that are hyper-thermostable, can outcompete
                      the native ligand (G-CSF), and bias cells toward
                      granulopoietic differentiation over triggering
                      proliferation. Furthermore, the design agonists
                      differentially modulate the kinetics and amplitudes of
                      signal transduction pathways, and gene expression patterns.
                      In contrast to G-CSF, they achieve more selective activation
                      of gene sets with hematopoietic functions with minimal
                      unwanted effects on immunomodulatory signaling. These
                      findings demonstrate the potential of dissecting the complex
                      G-CSFR signaling, and open up ways for new therapeutic
                      applications for designed cytokines.},
      cin          = {TU01},
      ddc          = {610},
      cid          = {I:(DE-He78)TU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40886048},
      doi          = {10.1016/j.ymthe.2025.08.031},
      url          = {https://inrepo02.dkfz.de/record/304282},
}