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000304282 1001_ $$aUllrich, Timo$$b0
000304282 245__ $$aTuning of G-CSFR signaling by de novo designed agonists.
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000304282 520__ $$aEnhancing 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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000304282 7001_ $$aPollmann, Christoph$$b1
000304282 7001_ $$aRitter, Malte$$b2
000304282 7001_ $$aHaaf, Jérémy$$b3
000304282 7001_ $$aAghaallaei, Narges$$b4
000304282 7001_ $$aTesakov, Ivan$$b5
000304282 7001_ $$aHatskovska, Valeriia$$b6
000304282 7001_ $$aEl-Riz, Maya$$b7
000304282 7001_ $$aMaksymenko, Kateryna$$b8
000304282 7001_ $$aKandabarau, Sergey$$b9
000304282 7001_ $$aKlimiankou, Maksim$$b10
000304282 7001_ $$0P:(DE-HGF)0$$aLengerke, Claudia$$b11
000304282 7001_ $$aWelte, Karl$$b12
000304282 7001_ $$aHernandez-Alvarez, Birte$$b13
000304282 7001_ $$aMüller, Patrick$$b14
000304282 7001_ $$aLupas, Andrei$$b15
000304282 7001_ $$aPiehler, Jacob$$b16
000304282 7001_ $$aSkokowa, Julia$$b17
000304282 7001_ $$aElGamacy, Mohammad$$b18
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