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PDBsum entry 2prj
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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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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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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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