Design of stimulus-responsive two-state hinge proteins
Open accessPublished version of a preprint
Abstract
In nature, proteins that switch between two conformations in response to environmental stimuli structurally transduce biochemical information in a manner analogous to how transistors control information flow in computing devices. Designing proteins with two distinct but fully structured conformations is a challenge for protein design as it requires sculpting an energy landscape with two distinct minima. Here we describe the design of “hinge” proteins that populate one designed state in the absence of ligand and a second designed state in the presence of ligand. X-ray crystallography, electron microscopy, double electron-electron resonance spectroscopy, and binding measurements demonstrate that despite the significant structural differences the two states are designed with atomic level accuracy and that the conformational and binding equilibria are closely coupled.
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- Authors
- Praetorius, F., Leung, P. J. Y., Tessmer, M. H., Broerman, A., Demakis, C., Dishman, A. F., Pillai, A., Idris, A., Juergens, D., Dauparas, J., Li, X., Levine, P. M., Lamb, M., Ballard, R. K., Gerben, S. R., Nguyen, H., Kang, A., Sankaran, B., Bera, A. K., Volkman, B. F., Nivala, J., Stoll, S., & Baker, D.
- Affiliations
- University of Washington (US)
- Lawrence Berkeley National Laboratory (US)
- Medical College of Wisconsin (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Praetorius, Florian
- Baker, David
- ORCID
- Praetorius, Florian
- Leung, Philip J. Y.
- Tessmer, Maxx H.
- Broerman, Adam
- Demakis, Cullen
- Dishman, Acacia F.
- Pillai, Arvind
- Idris, Abbas
- Juergens, David
- Dauparas, Justas
- Li, Xinting
- Levine, Paul M.
- Lamb, Mila
- Ballard, Ryanne K.
- Gerben, Stacey R.
- Nguyen, Hannah
- Kang, Alex
- Sankaran, Banumathi
- Bera, Asim K.
- Volkman, Brian F.
- Nivala, Jeff
- Stoll, Stefan
- Baker, David
- Venue
- Science
- Published
- 2023-08-18
- Volume
- 381
- Issue
- 6659
- Pages
- 754-760
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC10697137
- OpenAlex
- W4385930396
- Cited by
- 90
- References
- 8
- Citations by year
- 2026: 27 · 2025: 37 · 2024: 20 · 2023: 6
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Science Foundation (HDTRA1-19-1-0003, DEAC02-05CH11231, 2006864, DGE-214-0004, 2140004)
- Howard Hughes Medical Institute (DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DE-AC02-)
- Open Philanthropy Project
- National Energy Research Scientific Computing Center (DE–AC02–05CH11231, 05CH11231, AC02-05CH11231)
- National Institutes of Health (1s10od021557-01a1, DE-AC02–05CH11231)
- Defense Advanced Research Projects Agency (HR0011-21-2-0012, HR001120S0052, DE-AC02-05CH11231)
- Defense Threat Reduction Agency (DE-AC02-05CH11231, HDTRA1-19-1-0003, HDTRA1)
- Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
- National Institute of General Medical Sciences (R01GM125753, DE-AC02-05CH11231, GM125753)
- National Institute of Allergy and Infectious Diseases (R01AI168423)
- Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., AC02–05CH11231)
- Lawrence Berkeley National Laboratory (AC02‐05CH11231, DE-AC02-05CH11231, 05CH11231)
- 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 › Chemical Synthesis and Analysis
- Keywords
- protein design, two-state proteins, ligand binding, conformational switching, energy landscape, protein folding, protein conformational dynamics
- MeSH terms
- Ligands, Protein Conformation, Protein Engineering, Crystallography, X-Ray
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