Chemical control of metabolically-engineered voltage-gated K+ channels

Metabolic oligosaccharide engineering is a powerful approach for installing unnatural glycans with unique functional groups into the glycocalyx of living cells and animals. Using this approach, we showed that K+ channel complexes decorated with thiol-containing sialic acids were irreversibly inhibited with scorpion toxins bearing a pendant maleimide group. Irreversible inhibition required a glycosylated K+ channel subunit and was completely reversible with mild reductant when the tether connecting the toxin to the maleimide contained a disulfide bond. Cleavage of the disulfide bond not only restored function, but delivered a biotin moiety to the modified K+ channel subunit, providing a novel approach for preferentially labeling wild type K+ channel complexes functioning in cells.