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The spatial alignment of functional groups is a central aspect of most catalytic processes. Protein scaffolds with their exceptional molecular recognition properties have evolved into powerful biological catalysts. However, the rational design of artificial enzymes starting from non-catalytic protein domains proved challenging. Herein, we report the use of a non-enzymatic protein as template for amide bond formation. Starting from a protein adaptor domain capable of simultaneously binding to two peptide ligands, we designed a catalytic transfer reaction based on the native chemical ligation. This system was used for the selective labelling of a target protein validating its high chemoselectivity and potential as a novel tool for the selective covalent modification of proteins.

Molecular templates bind particular reactants, thereby increasing their effective concentrations and accelerating the corresponding reaction. This concept has been successfully applied to a number of chemical problems with a strong focus on nucleic acid templated reactions. We present the first protein-templated reaction that allows N-terminal linkage of two peptides. In the presence of a protein template, ligation reactions were accelerated by more than three orders of magnitude. The templated reaction is highly selective and proved its robustness in a protein-labeling reaction that was performed in crude cell lysate.