2prj
From Proteopedia
(New page: 200px<br /><applet load="2prj" size="450" color="white" frame="true" align="right" spinBox="true" caption="2prj, resolution 2.30Å" /> '''Binding of N-acetyl-...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2prj.jpg|left|200px]]<br /><applet load="2prj" size=" | + | [[Image:2prj.jpg|left|200px]]<br /><applet load="2prj" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2prj, resolution 2.30Å" /> | caption="2prj, resolution 2.30Å" /> | ||
'''Binding of N-acetyl-beta-D-glucopyranosylamine to Glycogen Phosphorylase B'''<br /> | '''Binding of N-acetyl-beta-D-glucopyranosylamine to Glycogen Phosphorylase B'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Structure-based drug design has led to the discovery of a number of | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 2PRJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with NBG, PLP and IMP as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 2PRJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus] with <scene name='pdbligand=NBG:'>NBG</scene>, <scene name='pdbligand=PLP:'>PLP</scene> and <scene name='pdbligand=IMP:'>IMP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1PRJ. Active as [http://en.wikipedia.org/wiki/Phosphorylase Phosphorylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.1 2.4.1.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2PRJ OCA]. |
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Acharya, K | + | [[Category: Acharya, K R.]] |
| - | [[Category: Bichard, C | + | [[Category: Bichard, C J.F.]] |
| - | [[Category: Fleet, G | + | [[Category: Fleet, G W.J.]] |
| - | [[Category: Johnson, L | + | [[Category: Johnson, L N.]] |
[[Category: Kontou, M.]] | [[Category: Kontou, M.]] | ||
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
| - | [[Category: Watson, K | + | [[Category: Watson, K A.]] |
| - | [[Category: Zographos, S | + | [[Category: Zographos, S E.]] |
[[Category: IMP]] | [[Category: IMP]] | ||
[[Category: NBG]] | [[Category: NBG]] | ||
| Line 27: | Line 27: | ||
[[Category: glycogen phosphorylase]] | [[Category: glycogen phosphorylase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:32:18 2008'' |
Revision as of 16:32, 21 February 2008
|
Binding of N-acetyl-beta-D-glucopyranosylamine to Glycogen Phosphorylase B
Overview
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.
About this Structure
2PRJ is a Single protein structure of sequence from Oryctolagus cuniculus with , and as ligands. This structure supersedes the now removed PDB entry 1PRJ. Active as Phosphorylase, with EC number 2.4.1.1 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
Page seeded by OCA on Thu Feb 21 18:32:18 2008
