Human Brain Hexokinase Type 1
Created by Spenser Angel
Human brain hexokinase type 1 (PDB ID= 1DGK) is an enzyme that regulates the rate of glycolysis in the brain of humans. By transfer of a phosphate group from ATP to a glucose molecule, hexokinase produces glucose-6-phosphate, the activated form of glucose needed for the glycolytic pathway (1).
Human hexokinase is a monomer that consists of two domains, an N-terminal domain and a C-terminal domain, connected by an alpha helix (2).
Human Hexokinase is an a/b protein, with alpha helices and beta sheets interspersed within the same subunit; these secondary structures are separated by turns and random coils (3).
The ligands of hexokinase are ADP (purple), glucose (red), and phosphate (light blue). The binding sites of these ligands are also home to serveral functionally important residues (green). In the ATP binding site, Thr-680 stabilizes the transition state from ATP to ADP; Asp-532 and Arg-539 holds ADP firmly in the active site (4).
The conversion of glucose to glucose-6-phosphate by human hexokinase is allosterically regulated. The product, glucose-6-phosphate, binds to the phosphate ligand on the N-terminal domain when concentrations of the product are high (5). The binding event transmits a signal through the alpha helix connecting the two domains, decreasing the affinity of the substrate, glucose, for the active site on the C-terminal domain(6). Many functionally important residues (yellow) are present at both of these active sites (1).
Human hexokinase exists in two stable conformations. Before the binding of glucose and ATP, the protein is in the open conformation, with the binding sites for ATP and glucose accessible. When glucose and ATP have both bound to the enzyme, the protein undergoes a conformational change into its closed conformation. In the closed conformation, the N-terminal domain and the C-terminal domain come together like a clam, with the connecting alpha helix as the hinge. The protein surrounds the active sites for glucose and ATP, preventing water from interacting with the active site and subsequently cleaving a phosphate group from the ADP molecule. The transfer of a phosphate group from ATP to the glucose molecule occurs when the enzyme is in the closed conformation. The "open" conformation shown here is a hexokinase complexed with glucose and phosphate (pdb id = 1hkc); the absence of ADP prevents the enzyme from assuming the completely closed conformation. The closed conformation shown here is hexokinase complexed with glucose and ADP (pdb id = 1dgk), and the molecule has assumed the completely closed conformation. Superimposition of the two molecules shows that the two domains come together more closely in the closed conformation (yellow), enabling the active site to be shielded from the interaction of water (7).
Arg-539 and Gly-679 are both functionally important residues; Arg-539 stabilizes the ADP-hexokinase unit, and Gly-679 is instrumental in the proper folding of the protein (8).
A Z-score of 58.1 and a root mean squared value of 1.5A (obtained from a Dali Server search) indicate that human pancreatic glucokinase ( pdb id= 3f9m) has a similar three-dimensional structure to human hexokinase (9). Superimposition of the two proteins shows the structural similarity between human pancreatic glucokinase (orange) and the C-terminus and connecting alpha helix of human brain hexokinase (white).