This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
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
