I would like to alter the activity of an enzyme towards a novel substrate.
I have a recently solved methyltransferase structure, which uses S-adenosylmethionine as a co-factor. There is also a substrate bound in the correct position for reaction. The part of that molecule which receives the methyl group is the same as in my novel substrate, but there are some major differences in the rest of the substrate. I can easily model the novel substrate into the active site in the conformation required to give the desired product, so I don't think that it is necessary to generate a transition state model.
What would be your recommendations to tackle this problem? I am thinking that the catalytic part of the active site (the SAM, the novel substrate, and the constellation of residues around the SAM and the conserved part of the substrate should be fixed, and only the positions around the altered part of the substrate should be re-designed. Does this seem reasonable?