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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Tsao, D; Diatchenko, L; Dokholyan, NV

Published Date

  • 2011

Published In

Volume / Issue

  • 6 / 8

Start / End Page

  • e24287 -

PubMed ID

  • 21904625

Pubmed Central ID

  • PMC3164188

Electronic International Standard Serial Number (EISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0024287

Language

  • eng

Conference Location

  • United States