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PDBsum entry 2amv
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* Residue conservation analysis
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Enzyme class:
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E.C.2.4.1.1
- glycogen phosphorylase.
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Pathway:
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Glycogen
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Reaction:
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[(1->4)-alpha-D-glucosyl](n) + phosphate = [(1->4)-alpha-D-glucosyl](n-1) + alpha-D-glucose 1-phosphate
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[(1->4)-alpha-D-glucosyl](n)
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+
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phosphate
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=
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[(1->4)-alpha-D-glucosyl](n-1)
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+
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alpha-D-glucose 1-phosphate
Bound ligand (Het Group name = )
matches with 63.16% similarity
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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
5:1413-1425
(1997)
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PubMed id:
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The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor.
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S.E.Zographos,
N.G.Oikonomakos,
K.E.Tsitsanou,
D.D.Leonidas,
E.D.Chrysina,
V.T.Skamnaki,
H.Bischoff,
S.Goldmann,
K.A.Watson,
L.N.Johnson.
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ABSTRACT
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BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the
reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An
alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor
of GP, and as such has potential to contribute to the regulation of glycogen
metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor
has no structural similarity to the natural regulators of GP. We have carried
out structural studies in order to elucidate the mechanism of inhibition.
RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show
that the compound (-)(S)-3-isopropyl
4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate
(Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to
AMP. The structure of the cocrystallised GPb-W1807 complex has been determined
at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287).
W1807 binds at the GPb allosteric effector site, the site which binds AMP,
glucose-6-phosphate and a number of other phosphorylated ligands, and induces
conformational changes that are characteristic of those observed with the
naturally occurring allosteric inhibitor, glucose-6-phosphate. The
dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands
that bind to the allosteric site and contact three arginine residues.
CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the
numerous nonpolar interactions made between the ligand and the protein. Its
potency as an inhibitor results from the induced conformational changes that
lock the enzyme in a conformation known as the T' state. Allosteric enzymes,
such as GP, offer a new strategy for structure-based drug design in which the
allosteric site can be exploited. The results reported here may have important
implications in the design of new therapeutic compounds.
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Selected figure(s)
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Figure 1.
Figure 1. The chemical structures of (a) 1-alkyl-1,4
dihydropyridine-2,3-dicarboxylic acid and (b) Bay W1807.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(1997,
5,
1413-1425)
copyright 1997.
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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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C.Tiraidis,
K.M.Alexacou,
S.E.Zographos,
D.D.Leonidas,
T.Gimisis,
and
N.G.Oikonomakos
(2007).
FR258900, a potential anti-hyperglycemic drug, binds at the allosteric site of glycogen phosphorylase.
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Protein Sci,
16,
1773-1782.
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PDB code:
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C.M.Lukacs,
N.G.Oikonomakos,
R.L.Crowther,
L.N.Hong,
R.U.Kammlott,
W.Levin,
S.Li,
C.M.Liu,
D.Lucas-McGady,
S.Pietranico,
and
L.Reik
(2006).
The crystal structure of human muscle glycogen phosphorylase a with bound glucose and AMP: an intermediate conformation with T-state and R-state features.
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Proteins,
63,
1123-1126.
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PDB code:
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G.Archontis,
K.A.Watson,
Q.Xie,
G.Andreou,
E.D.Chrysina,
S.E.Zographos,
N.G.Oikonomakos,
and
M.Karplus
(2005).
Glycogen phosphorylase inhibitors: a free energy perturbation analysis of glucopyranose spirohydantoin analogues.
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Proteins,
61,
984-998.
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N.G.Oikonomakos,
M.N.Kosmopoulou,
E.D.Chrysina,
D.D.Leonidas,
I.D.Kostas,
K.U.Wendt,
T.Klabunde,
and
E.Defossa
(2005).
Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs.
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Protein Sci,
14,
1760-1771.
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PDB codes:
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S.J.Teague
(2003).
Implications of protein flexibility for drug discovery.
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Nat Rev Drug Discov,
2,
527-541.
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S.H.Hansen,
and
J.G.McCormack
(2002).
Application of (13)C-filtered (1)H NMR to evaluate drug action on gluconeogenesis and glycogenolysis simultaneously in isolated rat hepatocytes.
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NMR Biomed,
15,
313-319.
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A.C.Anderson,
R.H.O'Neil,
T.S.Surti,
and
R.M.Stroud
(2001).
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
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Chem Biol,
8,
445-457.
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PDB code:
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J.L.Buchbinder,
V.L.Rath,
and
R.J.Fletterick
(2001).
Structural relationships among regulated and unregulated phosphorylases.
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Annu Rev Biophys Biomol Struct,
30,
191-209.
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J.L.Treadway,
P.Mendys,
and
D.J.Hoover
(2001).
Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus.
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Expert Opin Investig Drugs,
10,
439-454.
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N.G.Oikonomakos,
V.T.Skamnaki,
K.E.Tsitsanou,
N.G.Gavalas,
and
L.N.Johnson
(2000).
A new allosteric site in glycogen phosphorylase b as a target for drug interactions.
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Structure,
8,
575-584.
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PDB code:
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V.L.Rath,
M.Ammirati,
D.E.Danley,
J.L.Ekstrom,
E.M.Gibbs,
T.R.Hynes,
A.M.Mathiowetz,
R.K.McPherson,
T.V.Olson,
J.L.Treadway,
and
D.J.Hoover
(2000).
Human liver glycogen phosphorylase inhibitors bind at a new allosteric site.
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Chem Biol,
7,
677-682.
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PDB codes:
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K.E.Tsitsanou,
N.G.Oikonomakos,
S.E.Zographos,
V.T.Skamnaki,
M.Gregoriou,
K.A.Watson,
L.N.Johnson,
and
G.W.Fleet
(1999).
Effects of commonly used cryoprotectants on glycogen phosphorylase activity and structure.
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Protein Sci,
8,
741-749.
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PDB codes:
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N.G.Oikonomakos,
K.E.Tsitsanou,
S.E.Zographos,
V.T.Skamnaki,
S.Goldmann,
and
H.Bischoff
(1999).
Allosteric inhibition of glycogen phosphorylase a by the potential antidiabetic drug 3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarbo xylate.
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Protein Sci,
8,
1930-1945.
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PDB codes:
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M.Gregoriou,
M.E.Noble,
K.A.Watson,
E.F.Garman,
T.M.Krulle,
C.de la Fuente,
G.W.Fleet,
N.G.Oikonomakos,
and
L.N.Johnson
(1998).
The structure of a glycogen phosphorylase glucopyranose spirohydantoin complex at 1.8 A resolution and 100 K: the role of the water structure and its contribution to binding.
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Protein Sci,
7,
915-927.
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PDB codes:
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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
code is
shown on the right.
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Links
