Miniprotein-based artificial retr-oaldolase Łukasz Berlicki and Katarzyna Ozga Wroclaw University of Science and Technology, Poland
Miniproteins defined as proteins with molecular weights not exceeding 10 kDa and with stable tertiary structures can be used for the construction of functional molecules [1]. Several natural as well as de novo designed miniproteins have been already characterized structurally and shown to adopt a great variety of three-dimensional structures, which provides the basis for structure-based rational design [2]. Numerous examples of biologically active miniproteins are known including molecules with antiviral, anticancer, and analgesic properties [3]. The use of miniproteins for the development of catalysts remains, however, a virtually unexplored area. Here, we present a rational methodology for the construction of enzyme-like catalysts using a miniprotein scaffold. An highly active artificial retro-aldolase was obtained in a series of rounds of optimization that includedgrafting of the active motif in the cleft of the miniprotein, engineering the active site structure, and modifying the charge distribution on the surface of the miniprotein. References 1. Ożga, K.; Berlicki, Ł. Design and Engineering of Miniproteins. ACS Bio Med Chem Au 2022 , 2(4), 316-327. 2. Rocklin, G. J.; Chidyausiku, T. M.; Goreshnik, I.; Ford, A.; Houliston, S.; Lemak, A.; Carter, L.; Ravichandran, R.; Mulligan, V. K.; Chevalier, A.; Arrowsmith, C. H.; Baker, D. Global Analysis of Protein Folding Using Massively Parallel Design, Synthesis, and Testing. Science. 2017 , 357 (6347), 168–175. 3. Crook, Z. R.; Nairn, N. W.; Olson, J. M. Miniproteins as a Powerful Modality in Drug Development. Trends Biochem. Sci. 2020 , 45 (4), 332–346; 4. Ciesiołkiewicz, A.; Lizandra Perez, J.; Berlicki, Ł. Miniproteins in Medicinal Chemistry. Bioorg. Med. Chem. Lett. 2022 , 71, 128806.
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