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Hallucination of closed repeat proteins containing central pockets
Open accessPreprint — published as 10.1038/s41594-023-01112-6 · Paper page
Abstract
In pseudocyclic proteins such as TIM barrels, β barrels, and some helical transmembrane channels, a single subunit is repeated in a cyclic pattern, giving rise to a central cavity which can serve as a pocket for ligand binding or enzymatic activity. Inspired by these proteins, we devised a deep learning-based approach to broadly exploring the space of closed repeat proteins starting from only a specification of the repeat number and length. Biophysical data for 38 structurally diverse pseudocyclic designs produced in E. coli are consistent with the design models, and two crystal structures we were able to obtain are very close to the designed structures. Docking studies suggest the diversity of folds and central pockets provide effective starting points for designing small molecule binders or enzymes.
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Metadata
- Authors
- An, L., Hicks, D. R., Zorine, D., Dauparas, J., Wicky, B. I. M., Milles, L. F., Courbet, A., Bera, A. K., Nguyen, H., Kang, A., Carter, L., & Baker, D.
- Affiliations
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- An, Linna
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Publisher
- openRxiv
- Published
- 2022-09-02
- Volume
- 30
- Issue
- 11
- Pages
- 1755-1760
- ISSN
- 1545-9985 (ISSN-L)
- PMC
- PMC10643118
- OpenAlex
- W4387130982
- Cited by
- 15
- References
- 1
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 3
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense (DE-AC02-06CH11357, DE-AC02-05CH11231)
- Howard Hughes Medical Institute (DE-AC02-05CH11231)
- U.S. Department of Energy (DE‐ AC02‐06CH11357, -AC02-05CH11231, Contract No. DE-AC02-05-CH11231, S10OD018483, AC02‐06CH11357, 05CH11231, P30 GM124169, No. DE-AC02-05-CH11231, P30 GM124165, DE AC02 05CH11231, 06CH11357, GM124169, DE-AC02-)
- Washington Research Foundation (DE-AC02-06CH11357)
- Open Philanthropy Project
- National Energy Research Scientific Computing Center (DE–AC02–05CH11231, 05CH11231, AC02-05CH11231, Contract No. DE-AC02-05CH11231)
- National Institutes of Health (1s10od018483-01, DE-AC02–05CH11231, DE-AC02–06CH11357, GM124165, GM124169)
- Office of Science (P30 GM124165, No. DE-AC02- 05-CH11231, P30 GM124169, AC02‐06CH11357, DEAC02–05CH11231, AC02-05CH11231, DE-AC02, 05CH11231, 06CH11357, Contract No. DE-AC02-05CH11231, DE-AC02-06CH11357)
- National Institute on Aging (U19AG065156)
- National Institute of General Medical Sciences (DE-AC02-05CH11231, DE-AC02-06CH11357, GM124169, GM124165, S10OD018483, P30GM124169, P30GM124165)
- Basic Energy Sciences (S10OD018483, DE-AC02, 05CH11231, DE-AC02-05CH11231., DE-AC- 02-06CH11357, AC02‐06CH11357, AC02–05CH11231, 06CH11357)
- Biological and Environmental Research (05CH11231, DE-AC02 − 05CH11231, P30 GM124169, DEAC0206CH11357, S10OD018483, P30 GM124165, AC02-05CH11231)
- Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, DE-AC02-05CH11231, 06CH11357, P30 GM124165)
- Lawrence Berkeley National Laboratory (AC02‐05CH11231, DE-AC02-05CH11231, S10OD018483, DE-AC02-06CH11357, 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 › Structural Biology › Enzyme Structure and Function
- Keywords
- protein design, deep learning, TIM barrel, beta-barrel, central cavity, binding pocket, small-molecule binders, enzyme design, Escherichia coli, protein folding
- MeSH terms
- Hallucinations, Humans, Proteins
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