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De novo design of modular and tunable protein biosensors
Open accessAbstract
Naturally occurring protein switches have been repurposed for the development of biosensors and reporters for cellular and clinical applications 1. However, the number of such switches is limited, and reengineering them is challenging. Here we show that a general class of protein-based biosensors can be created by inverting the flow of information through de novo designed protein switches in which the binding of a peptide key triggers biological outputs of interest 2. The designed sensors are modular molecular devices with a closed dark state and an open luminescent state; analyte binding drives the switch from the closed to the open state. Because the sensor is based on the thermodynamic coupling of analyte binding to sensor activation, only one target binding domain is required, which simplifies sensor design and allows direct readout in solution. We create biosensors that can sensitively detect the anti-apoptosis protein BCL-2, the IgG1 Fc domain, the HER2 receptor, and Botulinum neurotoxin B, as well as biosensors for cardiac troponin I and an anti-hepatitis B virus antibody with the high sensitivity required to detect these molecules clinically. Given the need for diagnostic tools to track the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)3, we used the approach to design sensors for the SARS-CoV-2 spike protein and antibodies against the membrane and nucleocapsid proteins. The former, which incorporates a de novo designed spike receptor binding domain (RBD) binder 4, has a limit of detection of 15 pM and a luminescence signal 50-fold higher than the background level. The modularity and sensitivity of the platform should enable the rapid construction of sensors for a wide range of analytes, and highlights the power of de novo protein design to create multi-state protein systems with new and useful functions.
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“The modular nature of the miniprotein binders enables their rapid integration into designed diagnostic biosensors for both influenza and SARS-CoV-2 binders40.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [40]
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Diagnosing COVID-19: The Disease and Tools for Detection
Udugama, B. N., Kadhiresan, P., Kozlowski, H. N., Malekjahani, A., Osborne, M., Li, V. Y. C., Chen, H., Mubareka, S., Gubbay, J. B., & Chan, W. C. W. (2020) · ACS Nano · doi:10.1021/acsnano.0c02624 · Cited by 1,803
BCL-2 family proteins: changing partners in the dance towards death
Kale, J., Osterlund, E. J., & Andrews, D. W. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.186 · Cited by 1,574
NanoLuc Complementation Reporter Optimized for Accurate Measurement of Protein Interactions in Cells
Dixon, A. S., Schwinn, M. K., Hall, M. P., Zimmerman, K., Otto, P., Lubben, T. H., Butler, B. L., Binkowski, B. F., Machleidt, T., Kirkland, T. A., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00753 · Cited by 1,405
Structure-based design of prefusion-stabilized SARS-CoV-2 spikes
Hsieh, C.-L., Goldsmith, J. A., Schaub, J. M., DiVenere, A. M., Kuo, H.-C., Javanmardi, K., Le, K. C., Wrapp, D., Lee, A. G., Liu, Y., et al. (2020) · Science · doi:10.1126/science.abd0826 · Cited by 1,303
Self-citationDe novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Cao, L., Goreshnik, I., Coventry, B., Case, J. B., Miller, L., Kozodoy, L., Chen, R. E., Carter, L., Walls, A. C., Park, Y.-J., et al. (2020) · Science · doi:10.1126/science.abd9909 · Cited by 742
Self-citationRosettaScripts: A Scripting Language Interface to the Rosetta Macromolecular Modeling Suite
Fleishman, S. J., Leaver‐Fay, A., Corn, J. E., Strauch, E., Khare, S. D., Koga, N., Ashworth, J. R., Murphy, P. M., Richter, F. M., Lemmon, G., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020161 · Cited by 659
Self-citationAlgorithm discovery by protein folding game players
Khatib, F., Cooper, S., Tyka, M. D., Xu, K., Makedon, I., Popović, Z., Baker, D. A., & Players, F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115898108 · Cited by 593
Self-citationStructure-based Design of Prefusion-stabilized SARS-CoV-2 SpikesPreprint
Hsieh, C., Goldsmith, J., Schaub, J. M., et al. (2020) · bioRxiv · doi:10.1101/2020.05.30.125484 · Cited by 588
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Design of protein-binding proteins from the target structure alone
Cao, L., Coventry, B., Goreshnik, I., Huang, B., Sheffler, W., Park, J. S., Jude, K. M., Marković, I., Kadam, R. U., Verschueren, K. H. G., et al. (2022) · Nature · doi:10.1038/s41586-022-04654-9 · Cited by 577
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Learning inverse folding from millions of predicted structuresPreprint
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Lou, J., Jiao, Y., Yang, R., Huang, Y., Xu, X., Zhang, L., Ma, Z., Yu, Y., Peng, W., Yuan, Y., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2209218119 · Cited by 359
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Metadata
- Authors
- Quijano-Rubio, A., Yeh, H.-W., Park, J., Lee, H., Langan, R. A., Boyken, S. E., Lajoie, M. J., Cao, L., Chow, C. M., Miranda, M. C., Wi, J., Hong, H. J., Stewart, L., Oh, B.-H., & Baker, D.
- Affiliations
- University of Washington (US)
- Korea Advanced Institute of Science and Technology (KR)
- Kangwon National University (KR)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Oh, Byung-Ha
- Baker, David
- ORCID
- Venue
- Nature
- Published
- 2021-01-27
- Volume
- 591
- Issue
- 7850
- Pages
- 482-487
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8074680
- OpenAlex
- W3125484908
- Cited by
- 260
- References
- 57
- Citations by year
- 2026: 34 · 2025: 51 · 2024: 43 · 2023: 42 · 2022: 58 · 2021: 31
- FWCI
- 13.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Washington Research Foundation
- Open Philanthropy Project
- LG Yeonam Cultural Foundation
- National Institute on Aging (U19AG065156)
- National Institute of Allergy and Infectious Diseases (U01AI151698, AI151698)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › bioluminescence and chemiluminescence research
- Keywords
- de novo protein design, protein biosensors, protein switches, luminescent biosensors, HER2 receptor, botulinum neurotoxin B, cardiac troponin I, SARS-CoV-2 spike protein, spike protein receptor-binding domain, analyte binding
- MeSH terms
- SARS-CoV-2, Coronavirus Nucleocapsid Proteins, Coronavirus M Proteins, Antibodies, Viral, Botulinum Toxins, Hepatitis B virus, Immunoglobulin G, Phosphoproteins, Sensitivity and Specificity, Viral Matrix Proteins, Biosensing Techniques, Erb-b2 Receptor Tyrosine Kinases, Troponin I, Proto-Oncogene Proteins c-bcl-2, Luminescence, Limit of Detection, Spike Glycoprotein, Coronavirus
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