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PLoS One. 2011;6(8):e24287. doi: 10.1371/journal.pone.0024287. Epub 2011 Aug 31.

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

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1
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, United States of America.

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.

PMID:
21904625
PMCID:
PMC3164188
DOI:
10.1371/journal.pone.0024287
[Indexed for MEDLINE]
Free PMC Article
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