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In Situ Cyclization of Proteins (INCYPRO): Cross-Link Derivatization Modulates Protein Stability

[Image: see text] Protein macrocyclization represents a very efficient strategy to increase the stability of protein tertiary structures. Here, we describe a panel of novel C3-symmetric tris-electrophilic agents and their use for the cyclization of proteins. These electrophiles are reacted with a pr...

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Detalles Bibliográficos
Autores principales: Neubacher, Saskia, Saya, Jordy M., Amore, Alessia, Grossmann, Tom N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011175/
https://www.ncbi.nlm.nih.gov/pubmed/31790232
http://dx.doi.org/10.1021/acs.joc.9b02490
Descripción
Sumario:[Image: see text] Protein macrocyclization represents a very efficient strategy to increase the stability of protein tertiary structures. Here, we describe a panel of novel C3-symmetric tris-electrophilic agents and their use for the cyclization of proteins. These electrophiles are reacted with a protein domain harboring three solvent-exposed cysteine residues, resulting in the in situ cyclization of the protein (INCYPRO). We observe a clear dependency of cross-linking rates on the electrophilicity. All nine obtained cross-linked protein versions show considerably increased thermal stability (up to 29 °C increased melting temperature) when compared to that of the linear precursor. Most interestingly, the degree of stabilization correlates with the hydrophilicity of the cross-link. These results will support the development of novel cross-linked proteins and enable a more rational design process.