Design of novel granulopoietic proteins by topological rescaffolding

Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using...

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Bibliographic Details
Published in:PLoS biology 2020-12, Vol.18 (12), p.e3000919-e3000919
Main Authors: Hernandez Alvarez, Birte, Skokowa, Julia, Coles, Murray, Mir, Perihan, Nasri, Masoud, Maksymenko, Kateryna, Weidmann, Laura, Rogers, Katherine W, Welte, Karl, Lupas, Andrei N, Müller, Patrick, ElGamacy, Mohammad
Format: Article
Language:English
Subjects:
Binding sites
Biology and Life Sciences
Cell Differentiation
Cell surface
Cells, Cultured
Chains
Computational Biology - methods
Computational neuroscience
Design
Design and construction
Dimers
Epitopes
Erythropoietin
Granulocyte colony-stimulating factor
Granulocyte Colony-Stimulating Factor - pharmacology
Granulocytes
Granulocytes - cytology
Granulocytes - drug effects
Hemagglutinins
Hematopoiesis - drug effects
Hematopoiesis - physiology
Hematopoietic Stem Cells - cytology
Humans
Influenza
Innovations
Interleukins
Medicine and Health Sciences
Methods
Methods and Resources
Neurotoxins
Neutrophils
Nuclear matrix
Packaging
Physical Sciences
Protein engineering
Protein Engineering - methods
Proteins
Receptors
Research and Analysis Methods
Residues
Retrofitting
Scaffolds
Simulation
Steroids
Structure-Activity Relationship
Surface plasmon resonance
Technology application
Toxins
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Summary:Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using a rescaffolding strategy with the goal of achieving simpler and more stable proteins. All of the 4 experimentally tested designs were folded, monomeric, and stable, while the 2 determined structures agreed with the design models within less than 2.5 Å. Despite the lack of significant topological or sequence similarity to their natural granulopoietic counterpart, 2 designs bound to the granulocyte colony-stimulating factor (G-CSF) receptor and exhibited potent, but delayed, in vitro proliferative activity in a G-CSF-dependent cell line. Interestingly, the designs also induced proliferation and differentiation of primary human hematopoietic stem cells into mature granulocytes, highlighting the utility of our approach to develop highly active therapeutic leads purely based on computational design.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3000919