title: The active conformation of human glucokinase is not altered by allosteric activators.
abstract: Glucokinase (GK) catalyses the formation of glucose 6-phosphate from glucose and ATP. A specific feature of GK amongst hexokinases is that it can cycle between active and inactive conformations as a function of glucose concentration, resulting in a unique positive kinetic cooperativity with glucose, which turns GK into a unique key sensor of glucose metabolism, notably in the pancreas. GK is a target of antidiabetic drugs aimed at the activation of GK activity, leading to insulin secretion. Here, the first structures of a GK-glucose complex without activator, of GK-glucose-AMP-PNP and of GK-glucose-AMP-PNP with a bound activator are reported. All these structures are extremely similar, thus demonstrating that binding of GK activators does not result in conformational changes of the active protein but in stabilization of the active form of GK.
authors.affiliation: BioXtal, PX Unit, c/o AFMB, UMR 6098, Case 932, 163 Avenue de Luminy, 13288 Marseille CEDEX 09, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Petit
authors.forename: Mathias
authors.initials: M
authors.lastname: Antoine
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferry
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Amandine
authors.initials: A
authors.lastname: Lagarde
authors.forename: Laure
authors.initials: L
authors.lastname: Gluais
authors.forename: Renaud
authors.initials: R
authors.lastname: Vincentelli
authors.forename: Laurent
authors.initials: L
authors.lastname: Vuillard
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000737:chemistry / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003460:Crystallization; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D000266:Adenylyl Imidodiphosphate; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005947:Glucose