Douglas Tsao - Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase

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      Publication Details (including relevant citation   information):

      Tsao, D., Diatchenko, L., and Dokholyan, N. V., Public   Library of Science ONE, 6:e24287, (2011)

      Abstract:

      Methyltransferases   possess a homologous domain that requires both a divalent metal   cation and S-adenosyl-L-methionine (SAM) to catalyze its   reactions. The kinetics of several methyltransferases has been   well characterized; however, the details regarding their   structural mechanisms have remained unclear to date. Using   catechol O-methyltransferase (COMT) as a model, we perform   discrete molecular dynamics and computational docking simulations   to elucidate the initial stages of cofactor binding. We find that   COMT binds SAM via an induced-fit mechanism, where SAM adopts a   different docking pose in the absence of metal and substrate in   comparison to the holoenzyme. Flexible modeling of the active   site side-chains is essential for observing the lowest energy   state in the apoenzyme; rigid docking tools are unable to   recapitulate the pose unless the appropriate side-chain   conformations are given a priori. From our docking results, we   hypothesize that the metal reorients SAM in a conformation   suitable for donating its methyl substituent to the recipient   ligand. The proposed mechanism enables a general understanding of   how divalent metal cations contribute to methyltransferase   function.

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