“…To test this model, we sought a DNA substrate that would bind the DNMT domain and stabilize it in such a conformation. Extensive study of cytosine methylation by the M.HhaI methyltransferase has elucidated a precatalytic pathway in which the enzyme 1) binds its DNA substrate, 2) destabilizes the target cytosine, causing it to flip out of the DNA helix, and 3) undergoes a conformational rearrangement to close its catalytic loop, creating a 'closed' active site capable of methylation (Matje et al, 2011;Roberts and Cheng, 1998;Sankpal and Rao, 2002).…”