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

ABSTRACT: 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 ? -turns, decreased ? -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.

SUBMITTER: Yellapu NK 

PROVIDER: S-EPMC3586473 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature