Molecular insight into conformational transformation of human glucokinase: conventional and targeted molecular dynamics.

Journal of Biomolecular Structure & Dynamics
Elena Ermakova, Rauf Kurbanov

Abstract

Glucokinase (GK) plays a key role in the regulation of hepatic glucose metabolism. An unusual mechanism of positive cooperativity of monomeric GK containing only a single binding site for glucose is very interesting and still unclear. The activation process of GK is associated with a large-scale conformational change from the inactive to the active state. Here, conventional and targeted molecular dynamics simulations were used to study the conformational dynamics of GK in the stable configurations and in the transition from active to inactive state. Three phases of the structural reorganization of GK were detected. The first step is a transformation of GK from the active state to the intermediate structure, where the cleft between the domains is open, but alpha helix 13 is still inside the small domain. From this point, there are two alternative paths. One path leads to the inactive state through the release of helix 13 from the inside of small domain to the outside. Other path goes back to the active state. Simulation results reveal the critical role of helix 13 in the transformation of GK from the open state to inactive one and the influence of the loop 2 on the protein transformation between the open and the closed active st...Continue Reading

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Methods Mentioned

BETA
NMR
isothermal titration calorimetry
X-ray
PCA

Software Mentioned

CHARMM36
NAMD
VMD
CMD
CHARMM
TMD
carma
Modeller

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