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PDBsum entry 1prj
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Glycogen phosphorylase
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PDB id
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1prj
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References listed in PDB file
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Key reference
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Title
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N-Acetyl-Beta-D-Glucopyranosylamine: a potent t-State inhibitor of glycogen phosphorylase. A comparison with alpha-D-Glucose.
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Authors
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N.G.Oikonomakos,
M.Kontou,
S.E.Zographos,
K.A.Watson,
L.N.Johnson,
C.J.Bichard,
G.W.Fleet,
K.R.Acharya.
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Ref.
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Protein Sci, 1995,
4,
2469-2477.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
perfect match.
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Abstract
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Structure-based drug design has led to the discovery of a number of glucose
analogue inhibitors of glycogen phosphorylase that have an increased affinity
compared to alpha-D-glucose (Ki = 1.7 mM). The best inhibitor in the class of
N-acyl derivatives of beta-D-glucopyranosylamine,
N-acetyl-beta-D-glucopyranosylamine (1-GlcNAc), has been characterized by
kinetic, ultracentrifugation, and crystallographic studies. 1-GlcNAc acts as a
competitive inhibitor for both the b (Ki = 32 microM) and the a (Ki = 35 microM)
forms of the enzyme with respect to glucose 1-phosphate and in synergism with
caffeine, mimicking the binding of glucose. Sedimentation velocity experiments
demonstrated that 1-GlcNAc was able to induce dissociation of tetrameric
phosphorylase a and stabilization of the dimeric T-state conformation.
Co-crystals of the phosphorylase b-1-GlcNAc-IMP complex were grown in space
group P4(3)2(1)2, with native-like unit cell dimensions, and the complex
structure has been refined to give a crystallographic R factor of 18.1%, for
data between 8 and 2.3 A resolution. 1-GlcNAc binds tightly at the catalytic
site of T-state phosphorylase b at approximately the same position as that of
alpha-D-glucose. The ligand can be accommodated in the catalytic site with very
little change in the protein structure and stabilizes the T-state conformation
of the 280s loop by making several favorable contacts to Asn 284 of this loop.
Structural comparisons show that the T-state phosphorylase b-1-GlcNAc-IMP
complex structure is overall similar to the T-state phosphorylase
b-alpha-D-glucose complex structure. The structure of the 1-GlcNAc complex
provides a rational for the biochemical properties of the inhibitor.
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Secondary reference #1
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Title
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Design of inhibitors of glycogen phosphorylase: a study of alpha- And beta-C-Glucosides and 1-Thio-Beta-D-Glucose compounds.
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Authors
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K.A.Watson,
E.P.Mitchell,
L.N.Johnson,
J.C.Son,
C.J.Bichard,
M.G.Orchard,
G.W.Fleet,
N.G.Oikonomakos,
D.D.Leonidas,
M.Kontou.
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Ref.
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Biochemistry, 1994,
33,
5745-5758.
[DOI no: ]
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PubMed id
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