NDLI: Enzyme-like proteins by computational design

Content Provider	PubMed Central
Author	Bolon, Daniel N. Mayo, Stephen L.
Copyright Year	2001
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.
Related Links	http://dx.doi.org/10.1073/pnas.251555398
Ending Page	14279
Page Count	6
Starting Page	14274
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	98
Language	English
Publisher	The National Academy of Sciences
Publisher Date	2001-12-04
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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