Conformational transition pathway of R308K mutant glucokinase in the presence of the glucokinase activator YNKGKA4.

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.

Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study.

Glucokinase (GK) is the predominant hexokinase that acts as glucose sensor and catalyses the formation of Glucose-6-phosphate. The mutations in GK gene influence the affinity for glucose and lead to altered glucose levels in blood causing maturity onset diabetes of the young type 2 (MODY2) condition, which is one of the prominent reasons of type 2 diabetic condition. In view of the importance of mutated GK resulting in hyperglycemic condition, in the present study, molecular dynamics simulations were carried out in intact and 256 E-K mutated GK structures and their energy values and conformational variations were correlated. Energy variations were observed in mutated GK (3500 Kcal/mol) structure with respect to intact GK (5000 Kcal/mol), and it showed increased γ -turns, decreased ß -turns, and more helix-helix interactions that affected substrate binding region where its volume increased from 1089.152 Å(2) to 1246.353 Å(2). Molecular docking study revealed variation in docking scores (intact = -12.199 and mutated = -8.383) and binding mode of glucose in the active site of mutated GK where the involvement of A53, S54, K56, K256, D262 and Q286 has resulted in poor glucose binding which probably explains the loss of catalytic activity and the consequent prevailing of high glucose levels in MODY2 condition.