Tuning of granulopoietic signaling by de novo designed agonists
Tuning of granulopoietic signaling by de novo designed agonists
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 granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. Unlike G-CSF, they achieve 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. Graphical abstractbiorxiv;2023.11.25.568662v3/UFIG1F1ufig1
Aghaallaei Narges、Klimiankou Maksim、Welte Karl、Hernandez-Alvarez Birte、M¨1ller Patrick、Piehler Jacob、ElGamacy Mohammad、El-Riz Maya、Ullrich Timo、Lupas Andrei、Haaf J¨|r¨|my、Pollmann Christoph、Hatskovska Valeriia、Lengerke Claudia、Skokowa Julia、Kandabarau Sergey、Maksymenko Kateryna、Ritter Malte、Tesakov Ivan
Internal Medicine II, University Hospital T¨1bingen||Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of ViennaInternal Medicine II, University Hospital T¨1bingenInternal Medicine II, University Hospital T¨1bingen||University Children?ˉs Hospital T¨1bingenMax Planck Institute for Biology, Department Protein EvolutionFriedrich Miescher Laboratory of the Max Planck Society||ystems Biology of Development and Disease, University of KonstanzDepartment of Biology/Chemistry and Center for Cellular Nanoanalytics, Osnabr¨1ck UniversityMax Planck Institute for Biology, Department Protein Evolution||Internal Medicine II, University Hospital T¨1bingenDepartment of Biology/Chemistry and Center for Cellular Nanoanalytics, Osnabr¨1ck UniversityMax Planck Institute for Biology, Department Protein Evolution||Friedrich Miescher Laboratory of the Max Planck SocietyMax Planck Institute for Biology, Department Protein EvolutionInternal Medicine II, University Hospital T¨1bingenDepartment of Biology/Chemistry and Center for Cellular Nanoanalytics, Osnabr¨1ck UniversityMax Planck Institute for Biology, Department Protein Evolution||Internal Medicine II, University Hospital T¨1bingenInternal Medicine II, University Hospital T¨1bingenInternal Medicine II, University Hospital T¨1bingenInternal Medicine II, University Hospital T¨1bingenMax Planck Institute for Biology, Department Protein Evolution||Friedrich Miescher Laboratory of the Max Planck SocietyInternal Medicine II, University Hospital T¨1bingenInternal Medicine II, University Hospital T¨1bingen
基础医学生物科学研究方法、生物科学研究技术分子生物学
Aghaallaei Narges,Klimiankou Maksim,Welte Karl,Hernandez-Alvarez Birte,M¨1ller Patrick,Piehler Jacob,ElGamacy Mohammad,El-Riz Maya,Ullrich Timo,Lupas Andrei,Haaf J¨|r¨|my,Pollmann Christoph,Hatskovska Valeriia,Lengerke Claudia,Skokowa Julia,Kandabarau Sergey,Maksymenko Kateryna,Ritter Malte,Tesakov Ivan.Tuning of granulopoietic signaling by de novo designed agonists[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2023.11.25.568662.点此复制
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