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| 001 | 304282 | ||
| 005 | 20251107154044.0 | ||
| 024 | 7 | _ | |a 10.1016/j.ymthe.2025.08.031 |2 doi |
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| 100 | 1 | _ | |a Ullrich, Timo |b 0 |
| 245 | _ | _ | |a Tuning of G-CSFR signaling by de novo designed agonists. |
| 260 | _ | _ | |a Amsterdam |c 2025 |b Elsevier |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1762526417_1834969 |2 PUB:(DE-HGF) |
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| 500 | _ | _ | |a 2025 Nov 5;33(11):5741-5759 |
| 520 | _ | _ | |a 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. |
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| 700 | 1 | _ | |a Pollmann, Christoph |b 1 |
| 700 | 1 | _ | |a Ritter, Malte |b 2 |
| 700 | 1 | _ | |a Haaf, Jérémy |b 3 |
| 700 | 1 | _ | |a Aghaallaei, Narges |b 4 |
| 700 | 1 | _ | |a Tesakov, Ivan |b 5 |
| 700 | 1 | _ | |a Hatskovska, Valeriia |b 6 |
| 700 | 1 | _ | |a El-Riz, Maya |b 7 |
| 700 | 1 | _ | |a Maksymenko, Kateryna |b 8 |
| 700 | 1 | _ | |a Kandabarau, Sergey |b 9 |
| 700 | 1 | _ | |a Klimiankou, Maksim |b 10 |
| 700 | 1 | _ | |a Lengerke, Claudia |0 P:(DE-HGF)0 |b 11 |
| 700 | 1 | _ | |a Welte, Karl |b 12 |
| 700 | 1 | _ | |a Hernandez-Alvarez, Birte |b 13 |
| 700 | 1 | _ | |a Müller, Patrick |b 14 |
| 700 | 1 | _ | |a Lupas, Andrei |b 15 |
| 700 | 1 | _ | |a Piehler, Jacob |b 16 |
| 700 | 1 | _ | |a Skokowa, Julia |b 17 |
| 700 | 1 | _ | |a ElGamacy, Mohammad |b 18 |
| 773 | _ | _ | |a 10.1016/j.ymthe.2025.08.031 |g p. S1525001625006616 |0 PERI:(DE-600)2001818-6 |n 11 |p 5741-5759 |t Molecular therapy |v 33 |y 2025 |x 1525-0016 |
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