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PDBsum entry 2off
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References listed in PDB file
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Key reference
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Title
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Fr258900, A potential anti-Hyperglycemic drug, Binds at the allosteric site of glycogen phosphorylase.
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Authors
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C.Tiraidis,
K.M.Alexacou,
S.E.Zographos,
D.D.Leonidas,
T.Gimisis,
N.G.Oikonomakos.
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Ref.
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Protein Sci, 2007,
16,
1773-1782.
[DOI no: ]
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PubMed id
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Abstract
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FR258900 has been discovered as a novel inhibitor of human liver glycogen
phosphorylase a and proved to suppress hepatic glycogen breakdown and reduce
plasma glucose concentrations in diabetic mice models. To elucidate the
mechanism of inhibition, we have determined the crystal structure of the
cocrystallized rabbit muscle glycogen phosphorylase b-FR258900 complex and
refined it to 2.2 A resolution. The structure demonstrates that the inhibitor
binds at the allosteric activator site, where the physiological activator AMP
binds. The contacts from FR258900 to glycogen phosphorylase are dominated by
nonpolar van der Waals interactions with Gln71, Gln72, Phe196, and Val45' (from
the symmetry-related subunit), and also by ionic interactions from the
carboxylate groups to the three arginine residues (Arg242, Arg309, and Arg310)
that form the allosteric phosphate-recognition subsite. The binding of FR258900
to the protein promotes conformational changes that stabilize an inactive
T-state quaternary conformation of the enzyme. The ligand-binding mode is
different from those of the potent phenoxy-phthalate and acyl urea inhibitors,
previously described, illustrating the broad specificity of the allosteric site.
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Figure 3.
Figure 3. A schematic diagram of the T-state rmGPb dimeric molecule,
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Figure 7.
Figure 7. Comparison of the position of the inhibitor FR258900 as
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The above figures are
reprinted
by permission from the Protein Society:
Protein Sci
(2007,
16,
1773-1782)
copyright 2007.
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