ArticleProceedings of the National Academy of Sciences of the United States of America2001
Enzyme-like proteins by computational design.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 144 papers.
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Who cites it
144 citing papers in PubMed, 412 citations in OpenAlex.
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- Possibilities of Using De Novo Design for Generating Diverse Functional Food Enzymes.International journal of molecular sciences · 2023Review
- Computation-Aided Engineering of Cytochrome P450 for the Production of Pravastatin.ACS catalysis · 2022Article
- Natural Evolution Provides Strong Hints about Laboratory Evolution of Designer Enzymes.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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- Acyl Transfer Catalytic Activity in De Novo Designed Protein with N-Terminus of α-Helix As Oxyanion-Binding Site.Journal of the American Chemical Society · 2021Article
- Catalytic, theoretical, and biological investigation of an enzyme mimic model.Turkish journal of chemistry · 2021Article
84 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We report the development and initial experimental validation of a computational design procedure aimed at generating enzyme-like protein catalysts called "protozymes." Our design approach utilizes a "compute and build" strategy that is based on the physical/chemical principles governing protein stability and catalytic mechanism. By using the catalytically inert 108-residue Escherichia coli thioredoxin as a scaffold, the histidine-mediated nucleophilic hydrolysis of p-nitrophenyl acetate as a model reaction, and the ORBIT protein design software to compute sequences, an active site scan identified two promising catalytic positions and surrounding active-site mutations required for substrate binding. Experimentally, both candidate protozymes demonstrated catalytic activity significantly above background. One of the proteins, PZD2, displayed "burst" phase kinetics at high substrate concentrations, consistent with the formation of a stable enzyme intermediate. The kinetic parameters of PZD2 are comparable to early catalytic Abs. But, unlike catalytic Ab design, our design procedure is independent of fold, suggesting a possible mechanism for examining the relationships between protein fold and the evolvability of protein function.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.