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A topological refactoring design strategy yields highly stable granulopoietic proteins.

التفاصيل البيبلوغرافية
العنوان: A topological refactoring design strategy yields highly stable granulopoietic proteins.
المؤلفون: Skokowa J; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany. julia.skokowa@med.uni-tuebingen.de., Hernandez Alvarez B; Max Planck Institute for Biology, 72076, Tübingen, Germany., Coles M; Max Planck Institute for Biology, 72076, Tübingen, Germany., Ritter M; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Nasri M; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Haaf J; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Aghaallaei N; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Xu Y; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Mir P; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Krahl AC; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Rogers KW; Friedrich Miescher Laboratory of the Max Planck Society, 72076, Tübingen, Germany.; Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA., Maksymenko K; Max Planck Institute for Biology, 72076, Tübingen, Germany.; Friedrich Miescher Laboratory of the Max Planck Society, 72076, Tübingen, Germany., Bajoghli B; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Welte K; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany., Lupas AN; Max Planck Institute for Biology, 72076, Tübingen, Germany., Müller P; Friedrich Miescher Laboratory of the Max Planck Society, 72076, Tübingen, Germany.; Department of Biology, University of Konstanz, 78464, Konstanz, Germany., ElGamacy M; Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, 72076, Tübingen, Germany. mohammad.elgamacy@tuebingen.mpg.de.; Friedrich Miescher Laboratory of the Max Planck Society, 72076, Tübingen, Germany. mohammad.elgamacy@tuebingen.mpg.de.; Heliopolis Biotechnology Ltd, Cambridge, CB24 9RX, UK. mohammad.elgamacy@tuebingen.mpg.de.; Max Planck Institute for Biology, 72076, Tübingen, Germany. mohammad.elgamacy@tuebingen.mpg.de.
المصدر: Nature communications [Nat Commun] 2022 May 26; Vol. 13 (1), pp. 2948. Date of Electronic Publication: 2022 May 26.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Granulocyte Colony-Stimulating Factor*/genetics , Hematopoiesis*, Hematopoietic Stem Cells ; Humans ; Neutrophils
مستخلص: Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to design novel granulopoietic proteins starting from the granulocyte-colony stimulating factor (G-CSF) structure. We change a protein fold by rearranging the sequence and optimising it towards the new fold. Testing four designs, we obtain two that possess nanomolar activity, the most active of which is highly thermostable and protease-resistant, and matches its designed structure to atomic accuracy. While the designs possess starkly different sequence and structure from the native G-CSF, they show specific activity in differentiating primary human haematopoietic stem cells into mature neutrophils. The designs also show significant and specific activity in vivo. Our topological refactoring approach is largely independent of sequence or structural context, and is therefore applicable to a wide range of protein targets.
(© 2022. The Author(s).)
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المشرفين على المادة: 143011-72-7 (Granulocyte Colony-Stimulating Factor)
تواريخ الأحداث: Date Created: 20220526 Date Completed: 20220530 Latest Revision: 20221113
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9135769
DOI: 10.1038/s41467-022-30157-2
PMID: 35618709
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-022-30157-2