Abstract
Glucokinase (GK) plays a vital role in the control of blood glucose levels and its altered activity can lead to the development of forms of diabetes. We have previously identified a mutant GK (R308K) in patients with type 2 diabetes with reduced enzyme activity. In the present study, the activation mechanism of GK from super-open to the closed state under wild-type and mutant conditions in the presence of the novel aminophosphonate derivative YNKGKA4 (an allosteric activator of GK) was characterized via a series of molecular dynamics simulations. A reliable conformational transition pathway of GK was observed from super-open to closed state during trajectory analysis. Glucose was also observed to modulate its binding orientation in the active site but with stable moments in the cavity. These observations provide insights into the complicated conformational transitions in the presence of YNKGKA4 and the molecular mechanism of GK activators for the allosteric regulation of mutant forms of GK.