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PDBsum entry 1v4s
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Contents |
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* Residue conservation analysis
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Enzyme class:
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E.C.2.7.1.1
- hexokinase.
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Reaction:
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a D-hexose + ATP = a D-hexose 6-phosphate + ADP + H+
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D-hexose
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+
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ATP
Bound ligand (Het Group name = )
corresponds exactly
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=
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D-hexose 6-phosphate
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Structure
12:429-438
(2004)
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PubMed id:
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Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase.
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K.Kamata,
M.Mitsuya,
T.Nishimura,
J.Eiki,
Y.Nagata.
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ABSTRACT
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Glucokinase is a monomeric enzyme that displays a low affinity for glucose and a
sigmoidal saturation curve for its substrate, two properties that are important
for its playing the role of a glucose sensor in pancreas and liver. The
molecular basis for these two properties is not well understood. Herein we
report the crystal structures of glucokinase in its active and inactive forms,
which demonstrate that global conformational change, including domain
reorganization, is induced by glucose binding. This suggests that the positive
cooperativity of monomeric glucokinase obeys the "mnemonical
mechanism" rather than the well-known concerted model. These structures
also revealed an allosteric site through which small molecules may modulate the
kinetic properties of the enzyme. This finding provided the mechanistic basis
for activation of glucokinase as a potential therapeutic approach for treating
type 2 diabetes mellitus.
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Selected figure(s)
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Figure 6.
Figure 6. Kinetic Model of GlucokinaseGlucokinase appears
to exist in three conformations and to have two catalytic
cycles. The ratio of two catalytic cycles is responsible for the
sigmoidal response to glucose. Although ordered process in the
slow cycle of glucokinase was indicated by isotope-exchange
experiment, the addition of substrates in the fast cycle may be
random.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2004,
12,
429-438)
copyright 2004.
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Figure was
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.N.Volkov,
H.Barrios,
P.Mathonet,
C.Evrard,
M.Ubbink,
J.P.Declercq,
P.Soumillion,
and
J.Fastrez
(2011).
Engineering an Allosteric Binding Site for Aminoglycosides into TEM1-β-Lactamase.
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Chembiochem,
12,
904-913.
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PDB codes:
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M.L.Massa,
J.J.Gagliardino,
and
F.Francini
(2011).
Liver glucokinase: An overview on the regulatorymechanisms of its activity.
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IUBMB Life,
63,
1-6.
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Q.Liu,
Y.Shen,
S.Liu,
J.Weng,
and
J.Liu
(2011).
Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site.
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FEBS Lett,
585,
1175-1179.
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PDB code:
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S.Costantini,
P.Prandini,
M.Corradi,
A.Pasquali,
G.Contreas,
P.F.Pignatti,
L.Pinelli,
E.Trabetti,
and
C.Maffeis
(2011).
A novel synonymous substitution in the GCK gene causes aberrant splicing in an Italian patient with GCK-MODY phenotype.
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Diabetes Res Clin Pract,
92,
e23-e26.
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Z.Huang,
L.Zhu,
Y.Cao,
G.Wu,
X.Liu,
Y.Chen,
Q.Wang,
T.Shi,
Y.Zhao,
Y.Wang,
W.Li,
Y.Li,
H.Chen,
G.Chen,
and
J.Zhang
(2011).
ASD: a comprehensive database of allosteric proteins and modulators.
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Nucleic Acids Res,
39,
D663-D669.
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E.Ghafar-Zadeh,
S.F.Chowdhury,
A.Aliakbar,
V.Chodavarapu,
R.Lumbroso,
R.Lambrose,
L.K.Beitel,
L.Beital,
M.Sawan,
and
M.Trifiro
(2010).
Handheld impedance biosensor system using engineered proteinaceous receptors.
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Biomed Microdevices,
12,
967-975.
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J.A.Zorn,
and
J.A.Wells
(2010).
Turning enzymes ON with small molecules.
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Nat Chem Biol,
6,
179-188.
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M.Larion,
and
B.G.Miller
(2010).
Global fit analysis of glucose binding curves reveals a minimal model for kinetic cooperativity in human glucokinase.
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Biochemistry,
49,
8902-8911.
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S.J.Edelstein,
M.I.Stefan,
and
N.Le Novère
(2010).
Ligand depletion in vivo modulates the dynamic range and cooperativity of signal transduction.
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PLoS One,
5,
e8449.
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A.C.Bishop,
and
V.L.Chen
(2009).
Brought to life: targeted activation of enzyme function with small molecules.
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J Chem Biol,
2,
1-9.
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D.W.Pettigrew
(2009).
Amino acid substitutions in the sugar kinase/hsp70/actin superfamily conserved ATPase core of E. coli glycerol kinase modulate allosteric ligand affinity but do not alter allosteric coupling.
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Arch Biochem Biophys,
481,
151-156.
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D.W.Pettigrew
(2009).
Oligomeric interactions provide alternatives to direct steric modes of control of sugar kinase/actin/hsp70 superfamily functions by heterotropic allosteric effectors: inhibition of E. coli glycerol kinase.
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Arch Biochem Biophys,
492,
29-39.
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F.M.Matschinsky
(2009).
Assessing the potential of glucokinase activators in diabetes therapy.
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Nat Rev Drug Discov,
8,
399-416.
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J.Zhang,
C.Li,
T.Shi,
K.Chen,
X.Shen,
and
H.Jiang
(2009).
Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis.
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PLoS One,
4,
e6304.
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K.K.Osbak,
K.Colclough,
C.Saint-Martin,
N.L.Beer,
C.Bellanné-Chantelot,
S.Ellard,
and
A.L.Gloyn
(2009).
Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia.
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Hum Mutat,
30,
1512-1526.
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M.Pal
(2009).
Recent advances in glucokinase activators for the treatment of type 2 diabetes.
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Drug Discov Today,
14,
784-792.
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O.N.Demerdash,
M.D.Daily,
and
J.C.Mitchell
(2009).
Structure-based predictive models for allosteric hot spots.
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PLoS Comput Biol,
5,
e1000531.
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P.B.Iynedjian
(2009).
Molecular physiology of mammalian glucokinase.
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Cell Mol Life Sci,
66,
27-42.
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P.Wei,
M.Shi,
S.Barnum,
H.Cho,
T.Carlson,
and
J.D.Fraser
(2009).
Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells.
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Diabetologia,
52,
2142-2150.
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S.Sayed,
D.R.Langdon,
S.Odili,
P.Chen,
C.Buettger,
A.B.Schiffman,
M.Suchi,
R.Taub,
J.Grimsby,
F.M.Matschinsky,
and
C.A.Stanley
(2009).
Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.
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Diabetes,
58,
1419-1427.
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E.Di Cera
(2008).
Thrombin.
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Mol Aspects Med,
29,
203-254.
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I.Estalella,
M.A.Garcia-Gimeno,
A.Marina,
L.Castaño,
and
P.Sanz
(2008).
Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients.
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J Hum Genet,
53,
460-466.
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J.Molnes,
L.Bjørkhaug,
O.Søvik,
P.R.Njølstad,
and
T.Flatmark
(2008).
Catalytic activation of human glucokinase by substrate binding: residue contacts involved in the binding of D-glucose to the super-open form and conformational transitions.
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FEBS J,
275,
2467-2481.
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M.Coghlan,
and
B.Leighton
(2008).
Glucokinase activators in diabetes management.
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Expert Opin Investig Drugs,
17,
145-167.
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N.Tinto,
A.Zagari,
M.Capuano,
A.De Simone,
V.Capobianco,
G.Daniele,
M.Giugliano,
R.Spadaro,
A.Franzese,
and
L.Sacchetti
(2008).
Glucokinase gene mutations: structural and genotype-phenotype analyses in MODY children from South Italy.
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PLoS ONE,
3,
e1870.
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O.Anderka,
J.Boyken,
U.Aschenbach,
A.Batzer,
O.Boscheinen,
and
D.Schmoll
(2008).
Biophysical Characterization of the Interaction between Hepatic Glucokinase and Its Regulatory Protein: IMPACT OF PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTORS.
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J Biol Chem,
283,
31333-31340.
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V.Kumari,
and
C.Li
(2008).
Comparative docking assessment of glucokinase interactions with its allosteric activators.
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Curr Chem Genomics,
2,
76-89.
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C.D.Putnam,
M.Hammel,
G.L.Hura,
and
J.A.Tainer
(2007).
X-ray solution scattering (SAXS) combined with crystallography and computation: defining accurate macromolecular structures, conformations and assemblies in solution.
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Q Rev Biophys,
40,
191-285.
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C.M.García-Herrero,
M.Galán,
O.Vincent,
B.Flández,
M.Gargallo,
E.Delgado-Alvarez,
E.Blázquez,
and
M.A.Navas
(2007).
Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity.
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Diabetologia,
50,
325-333.
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E.Di Cera,
M.J.Page,
A.Bah,
L.A.Bush-Pelc,
and
L.C.Garvey
(2007).
Thrombin allostery.
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Phys Chem Chem Phys,
9,
1291-1306.
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E.Di Luccio,
B.Petschacher,
J.Voegtli,
H.T.Chou,
H.Stahlberg,
B.Nidetzky,
and
D.K.Wilson
(2007).
Structural and kinetic studies of induced fit in xylulose kinase from Escherichia coli.
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J Mol Biol,
365,
783-798.
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PDB codes:
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E.J.Jeong,
K.Park,
H.A.Joung,
C.S.Lee,
D.W.Seol,
B.H.Chung,
and
M.Kim
(2007).
Detection of glucose-induced conformational change in hexokinase II using fluorescence complementation assay.
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Biotechnol Lett,
29,
797-802.
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H.K.Leiros,
A.L.Pey,
M.Innselset,
E.Moe,
I.Leiros,
I.H.Steen,
and
A.Martinez
(2007).
Structure of phenylalanine hydroxylase from Colwellia psychrerythraea 34H, a monomeric cold active enzyme with local flexibility around the active site and high overall stability.
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J Biol Chem,
282,
21973-21986.
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PDB codes:
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J.F.Swain,
G.Dinler,
R.Sivendran,
D.L.Montgomery,
M.Stotz,
and
L.M.Gierasch
(2007).
Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker.
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Mol Cell,
26,
27-39.
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L.Bjørkhaug,
J.Molnes,
O.Søvik,
P.R.Njølstad,
and
T.Flatmark
(2007).
Allosteric activation of human glucokinase by free polyubiquitin chains and its ubiquitin-dependent cotranslational proteasomal degradation.
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J Biol Chem,
282,
22757-22764.
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M.C.Fyfe,
J.R.White,
A.Taylor,
R.Chatfield,
E.Wargent,
R.L.Printz,
T.Sulpice,
J.G.McCormack,
M.J.Procter,
C.Reynet,
P.S.Widdowson,
and
P.Wong-Kai-In
(2007).
Glucokinase activator PSN-GK1 displays enhanced antihyperglycaemic and insulinotropic actions.
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Diabetologia,
50,
1277-1287.
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M.F.Pino,
K.A.Kim,
K.D.Shelton,
J.Lindner,
S.Odili,
C.Li,
H.W.Collins,
M.Shiota,
F.M.Matschinsky,
and
M.A.Magnuson
(2007).
Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations.
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J Biol Chem,
282,
13906-13916.
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M.Wabitsch,
G.Lahr,
M.Van de Bunt,
C.Marchant,
M.Lindner,
J.von Puttkamer,
A.Fenneberg,
K.M.Debatin,
R.Klein,
S.Ellard,
A.Clark,
and
A.L.Gloyn
(2007).
Heterogeneity in disease severity in a family with a novel G68V GCK activating mutation causing persistent hyperinsulinaemic hypoglycaemia of infancy.
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Diabet Med,
24,
1393-1399.
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S.O.Adewole,
and
J.A.Ojewole
(2007).
Artocarpus communis Forst. root-bark aqueous extract- and streptozotocin-induced ultrastructural and metabolic changes in hepatic tissues of Wistar rats.
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Afr J Tradit Complement Altern Med,
4,
397-410.
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Y.Redko,
I.Li de Lasierra-Gallay,
and
C.Condon
(2007).
When all's zed and done: the structure and function of RNase Z in prokaryotes.
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Nat Rev Microbiol,
5,
278-286.
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C.Q.Diep,
G.Peng,
M.Bewley,
V.Pilauri,
I.Ropson,
and
J.E.Hopper
(2006).
Intragenic suppression of Gal3C interaction with Gal80 in the Saccharomyces cerevisiae GAL gene switch.
|
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Genetics,
172,
77-87.
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G.J.Coope,
A.M.Atkinson,
C.Allott,
D.McKerrecher,
C.Johnstone,
K.G.Pike,
P.C.Holme,
H.Vertigan,
D.Gill,
M.P.Coghlan,
and
B.Leighton
(2006).
Predictive blood glucose lowering efficacy by Glucokinase activators in high fat fed female Zucker rats.
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Br J Pharmacol,
149,
328-335.
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L.Härndahl,
D.Schmoll,
A.W.Herling,
and
L.Agius
(2006).
The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism.
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FEBS J,
273,
336-346.
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M.Futamura,
H.Hosaka,
A.Kadotani,
H.Shimazaki,
K.Sasaki,
S.Ohyama,
T.Nishimura,
J.Eiki,
and
Y.Nagata
(2006).
An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism.
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J Biol Chem,
281,
37668-37674.
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T.J.Lampidis,
M.Kurtoglu,
J.C.Maher,
H.Liu,
A.Krishan,
V.Sheft,
S.Szymanski,
I.Fokt,
W.R.Rudnicki,
K.Ginalski,
B.Lesyng,
and
W.Priebe
(2006).
Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells".
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Cancer Chemother Pharmacol,
58,
725-734.
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F.M.Matschinsky
(2005).
Glucokinase, glucose homeostasis, and diabetes mellitus.
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Curr Diab Rep,
5,
171-176.
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L.Pedelini,
M.A.Garcia-Gimeno,
A.Marina,
J.M.Gomez-Zumaquero,
P.Rodriguez-Bada,
S.López-Enriquez,
F.C.Soriguer,
A.L.Cuesta-Muñoz,
and
P.Sanz
(2005).
Structure-function analysis of the alpha5 and the alpha13 helices of human glucokinase: description of two novel activating mutations.
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Protein Sci,
14,
2080-2086.
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S.Kawai,
T.Mukai,
S.Mori,
B.Mikami,
and
K.Murata
(2005).
Hypothesis: structures, evolution, and ancestor of glucose kinases in the hexokinase family.
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J Biosci Bioeng,
99,
320-330.
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T.Mukai,
S.Kawai,
S.Mori,
B.Mikami,
and
K.Murata
(2004).
Crystal structure of bacterial inorganic polyphosphate/ATP-glucomannokinase. Insights into kinase evolution.
|
| |
J Biol Chem,
279,
50591-50600.
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PDB code:
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
