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Structural Mechanism of S-Adenosyl Methionine Binding to Catechol O-Methyltransferase.

Authors :
Tsao, Douglas
Diatchenko, Luda
Dokholyan, Nikolay V.
Source :
PLoS ONE. 2011, Vol. 6 Issue 8, p1-5. 5p.
Publication Year :
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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19326203
Volume :
6
Issue :
8
Database :
Academic Search Index
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
74399403
Full Text :
https://doi.org/10.1371/journal.pone.0024287