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PDBsum entry 2amv
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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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Authors
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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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Ref.
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Structure, 1997,
5,
1413-1425.
[DOI no: ]
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PubMed id
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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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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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Secondary reference #1
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Title
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Effects of commonly used cryoprotectants on glycogen phosphorylase activity and structure.
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Authors
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K.E.Tsitsanou,
N.G.Oikonomakos,
S.E.Zographos,
V.T.Skamnaki,
M.Gregoriou,
K.A.Watson,
L.N.Johnson,
G.W.Fleet.
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Ref.
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Protein Sci, 1999,
8,
741-749.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Glycogen phosphorylase b: description of the protein structure
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Authors
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K.R.Acharya,
D.I.Stuart,
K.M.Varvill,
L.N.Johnson.
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Ref.
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glycogen phosphorylase b: ...
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Secondary reference #3
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Title
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Crystallographic binding studies on the allosteric inhibitor glucose-6-Phosphate to t state glycogen phosphorylase b.
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Authors
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L.N.Johnson,
P.Snape,
J.L.Martin,
K.R.Acharya,
D.Barford,
N.G.Oikonomakos.
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Ref.
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J Mol Biol, 1993,
232,
253-267.
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PubMed id
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