Abstract
Combinations of biological macromolecules can provide researchers with precise control and unique methods for regulating, studying, and manipulating cellular processes. For instance, combining the unmatched encodability afforded by nucleic acids with the diverse functionality of proteins has transformed our approach to solving several problems in chemical biology. Despite these benefits, there remains a need for new methods to site-specifically generate conjugates between different classes of biomolecules. Here we present a fully enzymatic strategy for combining nucleic acids and proteins using SNAP-tag and RNA-TAG (transglycosylation at guanosine) technologies via a bifunctional preQ1-benzylguanine small molecule probe. We demonstrate the robust ability of this technology to assemble site-specific SNAP-tag - RNA conjugates with RNAs of varying length and use our conjugation strategy to recruit an endonuclease to an RNA of interest for targeted degradation. We foresee that combining SNAP-tag and RNA-TAG will facilitate researchers to predictably engineer novel macromolecular complexes.