Journal
NATURE CHEMICAL BIOLOGY
Volume 17, Issue 4, Pages 492-500Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-00699-x
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Funding
- Swiss initiative for systems biology (SystemsX.ch)
- European Research Council [716058]
- Swiss National Science Foundation [310030_163139]
- NCCR Molecular Systems Engineering
- NCCR Chemical Biology
- SNF/Innosuisse BRIDGE Proof-of-Concept grant
- EPFL Fellows postdoctoral fellowship
- Cluster of Excellence RESIST of the German Research foundation [EXC 2155]
- German Federal Ministry of Education and Research [01GM1503]
- German Center of Infection Research
- Swiss National Science Foundation (SNF) [310030_163139] Funding Source: Swiss National Science Foundation (SNF)
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This study successfully designed novel proteins using a bottom-up approach tailored to accommodate complex functional motifs. These proteins were functional components of biosensors and could modulate synthetic signaling receptors in engineered mammalian cells.
De novo protein design has enabled the creation of new protein structures. However, the design of functional proteins has proved challenging, in part due to the difficulty of transplanting structurally complex functional sites to available protein structures. Here, we used a bottom-up approach to build de novo proteins tailored to accommodate structurally complex functional motifs. We applied the bottom-up strategy to successfully design five folds for four distinct binding motifs, including a bifunctionalized protein with two motifs. Crystal structures confirmed the atomic-level accuracy of the computational designs. These de novo proteins were functional as components of biosensors to monitor antibody responses and as orthogonal ligands to modulate synthetic signaling receptors in engineered mammalian cells. Our work demonstrates the potential of bottom-up approaches to accommodate complex structural motifs, which will be essential to endow de novo proteins with elaborate biochemical functions, such as molecular recognition or catalysis.
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