'''Binding of N-acetyl-beta-D-glucopyranosylamine to Glycogen Phosphorylase B'''
===Binding of N-acetyl-beta-D-glucopyranosylamine to Glycogen Phosphorylase B===
==Overview==
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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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==About this Structure==
==About this Structure==
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[[Category: Zographos, S E.]]
[[Category: Zographos, S E.]]
[[Category: Glycogen phosphorylase]]
[[Category: Glycogen phosphorylase]]
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Revision as of 05:39, 28 July 2008
This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.
2PRJ is a Single protein structure of sequence from Oryctolagus cuniculus. This structure supersedes the now removed PDB entry 1prj. Full crystallographic information is available from OCA.
Reference
N-acetyl-beta-D-glucopyranosylamine: a potent T-state inhibitor of glycogen phosphorylase. A comparison with alpha-D-glucose., Oikonomakos NG, Kontou M, Zographos SE, Watson KA, Johnson LN, Bichard CJ, Fleet GW, Acharya KR, Protein Sci. 1995 Dec;4(12):2469-77. PMID:8580837
