title: Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site.
abstract: Human glucokinase (GK) plays an important role in glucose homeostasis. An E339K mutation in GK was recently found to be associated with hyperglycemia. It showed lower enzyme activity and impaired protein stability compared to the wild-type enzyme. Here, we present the crystal structure of E339K GK in complex with glucose. 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.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Shen
authors.forename: Sanling
authors.initials: S
authors.lastname: Liu
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006639:Histidine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D013912:Threonine; D012694:Serine; D006639:Histidine; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005947:Glucose