title: Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase.
abstract: Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 Å. GKRP binds to a super-open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Choi
authors.forename: Moon-Hyeong
authors.initials: MH
authors.lastname: Seo
authors.forename: Hyun-Ho
authors.initials: HH
authors.lastname: Kyeong
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Kim
authors.forename: Hak-Sung
authors.initials: HS
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000201:enzymology; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; C485100:GCKR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D029867:Xenopus Proteins; C499485:liver glucokinase regulatory protein, Xenopus; D005941:Glucokinase
keywords: hexokinase; sigmoidicity I conformational restriction; type 2 diabetes