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PDBsum entry 1k08
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Contents |
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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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Binding of n-Acetyl-N '-Beta-D-Glucopyranosyl urea and n-Benzoyl-N '-Beta-D-Glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies.
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Authors
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N.G.Oikonomakos,
M.Kosmopoulou,
S.E.Zographos,
D.D.Leonidas,
E.D.Chrysina,
L.Somsák,
V.Nagy,
J.P.Praly,
T.Docsa,
B.Tóth,
P.Gergely.
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Ref.
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Eur J Biochem, 2002,
269,
1684-1696.
[DOI no: ]
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PubMed id
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Abstract
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Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea
(Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been
identified as inhibitors of glycogen phosphorylase, a potential target for
therapeutic intervention in type 2 diabetes. To elucidate the structural basis
of inhibition, we determined the structure of muscle glycogen phosphorylase b
(GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution,
respectively. The structure of the GPb-Acurea complex reveals that the inhibitor
can be accommodated in the catalytic site of T-state GPb with very little change
in the tertiary structure. The glucopyranose moiety makes the standard hydrogen
bonds and van der Waals contacts as observed in the GPb-glucose complex, while
the acetyl urea moiety is in a favourable electrostatic environment and makes
additional polar contacts with the protein. The structure of the GPb-Bzurea
complex shows that Bzurea binds tightly at the catalytic site and induces
substantial conformational changes in the vicinity of the catalytic site. In
particular, the loop of the polypeptide chain containing residues 282-287 shifts
1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new
allosteric site, some 33 A from the catalytic site, which is currently the
target for the design of antidiabetic drugs.
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Figure 4.
Fig. 4. Stereo diagrams showing (A ) a comparison of
Acurea bound to GPb (orange) with native GPb (white) in the
vicinity of the catalytic site, and (B ) a comparison of Bzurea
(orange) bound to GPb with native GPb (white) in the vicinity of
the catalytic site.
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Figure 8.
Fig. 8. Stereo diagram showing a comparison of Bzurea
bound to GPb with CP320626 bound to GPb in the vicinity of the
new allosteric site. Green: GPb–Bzurea complex (subunit 1);
cyan: GPb–Bzurea complex (subunit 2); white:
GPb–glucose–CP320626 complex. All figures were produced
using xobjects (M. E. M. Noble, Laboratory of Molecular
Biophysics, University of Oxford, UK, unpublished results).
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The above figures are
reprinted
by permission from the Federation of European Biochemical Societies:
Eur J Biochem
(2002,
269,
1684-1696)
copyright 2002.
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Secondary reference #1
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Title
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A new allosteric site in glycogen phosphorylase b as a target for drug interactions.
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Authors
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N.G.Oikonomakos,
V.T.Skamnaki,
K.E.Tsitsanou,
N.G.Gavalas,
L.N.Johnson.
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Ref.
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Structure, 2000,
8,
575-584.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. The chemical structures of (a) CP91149 and (b)
CP320626, showing the numbering system used.
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The above figure is
reproduced from the cited reference
with permission from Cell Press
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