Mutations in GKRP

Mutation in E339K of glucokinase

An E339K mutation was recently found to be associated with hyperglycemia. It showed lower enzyme activity and impaired protein stability compared to the wild-type enzyme.

The mutation in Glu 339 of the glucokinase protein is highlighted cyan. This mutation results in a conformational change of His416, spatially interfering with adenosine-triphosphate (ATP) binding. Furthermore, Ser411 at the ATP binding site is phosphorylated and then hydrogen bonded with Thr82, physically blocking the ATP binding. These findings provide structural basis for the reduced activity of this mutant.

Liu, Q., Shen, Y., Liu, S., Weng, J., Liu, J. Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site. Febs Lett. 2011 (PubMed)

3QIC (PDB)

Mutation in Pro446 of GKRP



                        Mutation in Pro446 of the glucokinase regulatory protein
                        is linked to hypertriglyceridemia - a condition in which
                        triglyceride levels are elevated, often caused or
                        exacerbated by uncontrolled diabetes mellitus, obesity,
                        and sedentary habits. This condition is a risk factor
                        for coronary artery disease (CAD).

Pro446 mutation is shown in red. This proline residue is important for a kink, substituition of which impairs GKPR-mediated regulation of GCK. This residue is near catalytic side and its mutation will change the structure and impair regions of GCK-GKRP to interact.

Beck T, Miller BG. Structural Basis for Regulation of Human Glucokinase by Glucokinase Regulatory Protein. J. Biochemistry 2013 (PubMed)

4LC9 (PDB)

Intro