TY - JOUR
T1 - A QM/MM study of the phosphoryl transfer to the Kemptide substrate catalyzed by protein kinase A. the effect of the phosphorylation state of the protein on the mechanism
AU - Montenegro, Manuel
AU - Garcia-Viloca, Mireia
AU - Lluch, José M.
AU - González-Lafont, Àngels
PY - 2011/1/14
Y1 - 2011/1/14
N2 - We present here a theoretical study of the phosphoryl transfer catalytic mechanism of protein kinase A, which is the best known member of the large protein kinase family. We have built different theoretical models of the complete PKA-Mg2-ATP-substrate system to explore the two most accepted reaction pathways, using for the first time in a reaction mechanism theoretical study, the heptapeptide substrate Kemptide, which is relevant for its high efficiency and small size. The effect of the protein configuration, as modeled by two different X-ray structures with different phosphorylation states and degrees of flexibility, has been analyzed. The results indicate that the environmental conditions can influence the availability of the pathways and thus the choice of the mechanism to be followed. In addition, the roles of the two active site conserved residues, Asp166 and Lys168, have been analyzed for each reaction mechanism. © 2011 the Owner Societies.
AB - We present here a theoretical study of the phosphoryl transfer catalytic mechanism of protein kinase A, which is the best known member of the large protein kinase family. We have built different theoretical models of the complete PKA-Mg2-ATP-substrate system to explore the two most accepted reaction pathways, using for the first time in a reaction mechanism theoretical study, the heptapeptide substrate Kemptide, which is relevant for its high efficiency and small size. The effect of the protein configuration, as modeled by two different X-ray structures with different phosphorylation states and degrees of flexibility, has been analyzed. The results indicate that the environmental conditions can influence the availability of the pathways and thus the choice of the mechanism to be followed. In addition, the roles of the two active site conserved residues, Asp166 and Lys168, have been analyzed for each reaction mechanism. © 2011 the Owner Societies.
U2 - 10.1039/c0cp01062f
DO - 10.1039/c0cp01062f
M3 - Article
VL - 13
SP - 530
EP - 539
IS - 2
ER -