O-Methylation represents a prevalent tailoring modification in natural product biosynthesis, significantly altering molecular properties and bioactivity. In this study, we report the crystal structure of the O-methyltransferase (MTase) McbD in complex with S-adenosyl-l-homocysteine (SAH) at 3.0 Å resolution, complemented by a modeled binding pose for the substrate marinacarboline B (1). Through integrated site-directed mutagenesis and enzymatic assays, we identified critical residues required for catalytic activity and propose a refined mechanistic model for methyl transfer. These findings offer substantive structural and mechanistic insights into how O-MTases drive the diversification of bioactive natural products.
Qiao et al. (Mon,) studied this question.