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Design of proteins using rigid organic macrocycles as scaffolds

TitleDesign of proteins using rigid organic macrocycles as scaffolds
Publication TypeJournal Article
Year of Publication1999
AuthorsCauston, AS, Sherman, JC
JournalBioorganic & Medicinal Chemistry
Volume7
Pagination23-27
Date PublishedJan
Type of ArticleArticle
ISBN Number0968-0896
Keywords4-HELIX BUNDLE PROTEIN, ASSEMBLED SYNTHETIC PROTEINS, CHEMOSELECTIVE LIGATION, CONSTRUCTION, CROSS-LINKING, CRYSTAL-STRUCTURE, cyclotribenzylene, de novo protein, DE-NOVO PROTEINS, HELICAL BUNDLES, HELICAL PROTEIN, PEPTIDE, TASP, TEMPLATE
Abstract

We have designed and synthesized new three-helix template-assembled synthetic proteins (TASPs) 1a-c. The template was the rigid cyclotribenzylene (CTB) macrocycle 2, which has C-3 symmetry. Thiol moieties on the CTB template were used to link cysteine-containing peptide strands 3a-c via disulfide bonds. With designed peptide strands of 15 and 18 residues in length, the structure of TASPs 1a-c were determined to be helical in water according to circular dichroism (CD) spectroscopy. The helicities of TASPs la-e were unchanged over large ranges of pH (2-12) and salt concentrations (0-2 M KCl). TASPs 1a-c were also extremely resistant to chemical denaturants: it requires a guanidine hydrochloride (GnHCl) concentration of 7.4 M for TASPs 1a-c to lose 50% of their helicity. The major force for stabilization of TASPs 1a-c is the hydrophobic bundling of the helices. (C) 1999 Elsevier Science Ltd. All rights reserved.

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