Computational design of a modular protein sense/response system
By A. Glasgow, Yao-ming Huang, Daniel J. Mandell, Michael J. Thompson, Ryan S. Ritterson, Amanda L. Loshbaugh, J. Pellegrino, C. Krivacic, Roland A. Pache, Kyle A. Barlow and 5 more. 2019
124 citations recorded by the source corpus.
Sense and respond Many signaling pathways start with cellular proteins sensing and responding to small molecules. Despite advances in protein design, creating a protein-based sense-and-respond system remains challenging. Glasgow et al. designed binding sites at the interface of protein heterodimers (see the Perspective by Chica). By fusing each monomer to one half of a split reporter, they linked ligand-driven dimerization to the reporter output. The computational design strategy provides a generalizable approach to create synthetic sensing systems with different outputs. Science, this issue p. 1024; see also p. 952 Engineering de novo binding sites creates synthetic signaling systems that respond to specified small-molecule inputs. Sensing and responding to signals is a fundamental ability of living systems, but despite substantial progress in the computational design of new protein structures, there is no general approach for engineering arbitrary new protein sensors. Here, we describe a generalizable computational strategy for designing sensor-actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces and coupling ligand sensing to modular actuation through split reporters. Using this approach, we designed protein sensors that respond to farnesyl pyrophosphate, a metabolic intermediate in the production of valuable compounds. The sensors are functional in vitro and in cells, and the crystal structure of the engineered binding site closely matches the design model. Our computational design strategy opens broad avenues to link biological outputs to new signals.
Subfields: Cell Biology, Molecular Biology, Organic Chemistry
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In Cell Biology
In Molecular Biology
- Xingjie Pan
- Hamed Khakzad
- S. Rosset
- Bruno E. Correia
- Casper A. Goverde
- Benedict Wolf
- Tanja Kortemme
- David Baker
In Organic Chemistry
Citations in the corpus
- Recent advances in de novo protein design: Principles, methods, and applications (2021, background): “Highly stable helical bundles (58) 9 5 5 5 3 Ideal α-β proteins (30) 54 45 32 17 16 5 Ideal α-β proteins (61) 72 64 47 39 17 6 Proteins with curved β-sheets (62) 66 58 53 54 25 8 Proteins with the jelly roll topology (31) 19 16 2 2 2 1 Novel helical folds (36) 11 8 4 4 2 FoldIt player designed prote”
- De novo protein design by inversion of the AlphaFold structure prediction network (2022, background): “Backbone and side-chain rotamer conformations of the residues are sampled and scored with various scoring functions allowing the creation of new protein structures and functions such as zinc finger domains (Dahiyat & Mayo, 1997), protein sensors (Feng et al., 2015; Glasgow et al., 2019), enzymes (Ji”