title: Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase.
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.
authors: Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors: Douglas
authors: D
authors: Tsao
authors: Luda
authors: L
authors: Diatchenko
authors: Nikolay V
authors: NV
authors: Dokholyan
mesh_terms: D002394:Catechol O-Methyltransferase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012436:S-Adenosylmethionine / Q000378:metabolism*
chemical_list: D012436:S-Adenosylmethionine; D002394:Catechol O-Methyltransferase