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

Douglas Tsao, Luda Diatchenko, Nikolay V. Dokholyan

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere24287
JournalPloS one
Volume6
Issue number8
DOIs
StatePublished - Sep 7 2011

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catechol O-methyltransferase
Catechol O-Methyltransferase
S-adenosylmethionine
S-Adenosylmethionine
Methionine
methionine
methyltransferases
Methyltransferases
Metals
Divalent Cations
Conformations
Cations
cations
metals
Apoenzymes
Holoenzymes
apoproteins
molecular dynamics
Molecular Dynamics Simulation
active sites

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase. / Tsao, Douglas; Diatchenko, Luda; Dokholyan, Nikolay V.

In: PloS one, Vol. 6, No. 8, e24287, 07.09.2011.

Research output: Contribution to journalArticle

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