The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.
Automated Design of Efficient and Functionally Diverse Enzyme Repertoires
Open accessAbstract
Summary Substantial improvements in enzyme activity demand multiple mutations at spatially proximal positions in the active site. Such mutations, however, often exhibit unpredictable epistatic (non-additive) effects on activity. Here, we describe FuncLib - an automated method for designing multipoint mutations at enzyme active sites using phylogenetic analysis and Rosetta design calculations. We applied FuncLib to two unrelated enzymes, a phosphotriesterase and an acetyl-CoA synthetase. All designs were active and most showed activity profiles that significantly differed from the wild type and from one another. Several dozen designs with only 3-6 active-site mutations exhibited 10-4,000-fold higher efficiencies with a range of alternative substrates, including the hydrolysis of the toxic organophosphate nerve agents soman and cyclosarin and the synthesis of butyryl-CoA. FuncLib is implemented as a web-server (http://FuncLib.weizmann.ac.il); it circumvents iterative, high-throughput screens and opens the way to design highly efficient and diverse catalytic repertoires.
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Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Towards automated crystallographic structure refinement with phenix.refine
Afonine, P. V., Grosse-Kunstleve, R. W., Echols, N., Headd, J. J., Moriarty, N. W., Mustyakimov, M., Terwilliger, T. C., Urzhumtsev, A., Zwart, P. H., & Adams, P. D. (2012) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444912001308 · Cited by 5,511
Robustness–epistasis link shapes the fitness landscape of a randomly drifting protein
Bershtein, S., Segal, M., Bekerman, R., Tokuriki, N., & Tawfik, D. S. (2006) · Nature · doi:10.1038/nature05385 · Cited by 414 · cited 3×
“These results demonstrate that the combination of PROSS and FuncLib may not exhibit the stability threshold bottlenecks that have constrained the laboratory evolution of many enzymes, including PTE (Bershtein et al., 2006; Bloom et al., 2006; Goldsmith et al., 2017; Goldenzweig and Fleishman, 2018).”
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Jackson, C. J., Foo, J.-L., Tokuriki, N., Afriat, L., Carr, P. D., Kim, H.-K., Schenk, G., Tawfik, D. S., & Ollis, D. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907548106 · Cited by 119
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Combinatorial assembly and design of enzymes
Lipsh-Sokolik, R., Khersonsky, O., Schröder, S. P., de Boer, C., Hoch, S.-Y., Davies, G. J., Overkleeft, H. S., & Fleishman, S. J. (2023) · Science · doi:10.1126/science.ade9434 · Cited by 78
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Assessing and enhancing foldability in designed proteins
Listov, D., Lipsh‐Sokolik, R., Rosset, S., Yang, C., Correia, B. E., & Fleishman, S. J. (2022) · Protein Science · doi:10.1002/pro.4400 · Cited by 24
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Metadata
- Authors
- Khersonsky, O., Lipsh, R., Avizemer, Z., Ashani, Y., Goldsmith, M., Leader, H., Dym, O., Rogotner, S., Trudeau, D. L., Prilusky, J., Amengual-Rigo, P., Guallar, V., Tawfik, D. S., & Fleishman, S. J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 72
- Issue
- 1
- Pages
- 178-186.e5
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2893054519
- Cited by
- 297
- References
- 4
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Khersonsky, O., Lipsh, R., Avizemer, Z., Ashani, Y., Goldsmith, M., Leader, H., Dym, O., Rogotner, S., Trudeau, D. L., Prilusky, J., Amengual-Rigo, P., Guallar, V., Tawfik, D. S., & Fleishman, S. J. (2018). Automated Design of Efficient and Functionally Diverse Enzyme Repertoires. Molecular Cell. https://doi.org/10.1016/j.molcel.2018.08.033
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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