Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases

Chalcone O-methyltransferase (ChOMT) and isoflavone O-methyltransferase (IOMT) are S-adenosyl-L-methionine (SAM) dependent plant natural product methyltransferases involved in secondary metabolism in Medicago sativa (alfalfa), Here we report the crystal structure of ChOMT in complex with the product S-adenosyl-L-homocysteine and the substrate isoliquiritigenin (4,2',4'-trihydroxychalcone) refined to 1.8 Angstrom as well as the crystal structure of IOMT in complex with the products S-adenosyl-L-homocysteine and isoformononetin (4'-hydroxy-7-methoxyisoflavone) refined to 1.4 Angstrom. These two OMTs constitute the first plant methyltransferases to be structurally characterized and reveal a novel oligomerization domain and the molecular determinants for substrate selection. As such, this work provides a structural basis for understanding the substrate specificity of the diverse family of plant OMTs and facilitates the engineering of novel activities in this extensive class of natural product biosynthetic enzymes.