1fty
From Proteopedia
(New page: 200px<br /><applet load="1fty" size="450" color="white" frame="true" align="right" spinBox="true" caption="1fty, resolution 2.38Å" /> '''STRUCTURES OF GLYCOG...) |
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| - | [[Image:1fty.gif|left|200px]]<br /><applet load="1fty" size=" | + | [[Image:1fty.gif|left|200px]]<br /><applet load="1fty" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1fty, resolution 2.38Å" /> | caption="1fty, resolution 2.38Å" /> | ||
'''STRUCTURES OF GLYCOGEN PHOSPHORYLASE-INHIBITOR COMPLEXES AND THE IMPLICATIONS FOR STRUCTURE-BASED DRUG DESIGN'''<br /> | '''STRUCTURES OF GLYCOGEN PHOSPHORYLASE-INHIBITOR COMPLEXES AND THE IMPLICATIONS FOR STRUCTURE-BASED DRUG DESIGN'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Glycogen phosphorylase (GP) is currently exploited as a target for | + | Glycogen phosphorylase (GP) is currently exploited as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Spirohydantoin of glucopyranose and N-acetyl-beta-D-glucopyranosylamine have been identified as the most potent inhibitors of GP that bind at the catalytic site. Four spirohydantoin and three beta-D-glucopyranosylamine analogs have been designed, synthesized and tested for inhibition of GP in kinetic experiments. Depending on the functional group introduced, the K(i) values varied from 16.5 microM to 1200 microM. In order to rationalize the kinetic results, we determined the crystal structures of the analogs in complex with GP. All the inhibitors bound at the catalytic site of the enzyme, by making direct and water-mediated hydrogen bonds with the protein and by inducing minor movements of the side chains of Asp283 and Asn284, of the 280s loop that blocks access of the substrate glycogen to the catalytic site, and changes in the water structure in the vicinity of the site. The differences observed in the Ki values of the analogs can be interpreted in terms of variations in hydrogen bonding and van der Waals interactions, desolvation effects, ligand conformational entropy, and displacement of water molecules on ligand binding to the catalytic site. |
==About this Structure== | ==About this Structure== | ||
| - | 1FTY 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 GL7 and PLP as [http://en.wikipedia.org/wiki/ligands ligands]. 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:// | + | 1FTY 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=GL7:'>GL7</scene> and <scene name='pdbligand=PLP:'>PLP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1FTY OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Fleet, G | + | [[Category: Fleet, G W.]] |
[[Category: Gregoriou, M.]] | [[Category: Gregoriou, M.]] | ||
| - | [[Category: Johnson, L | + | [[Category: Johnson, L N.]] |
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
| - | [[Category: Skamnaki, V | + | [[Category: Skamnaki, V T.]] |
| - | [[Category: Tsitsanou, K | + | [[Category: Tsitsanou, K E.]] |
| - | [[Category: Watson, K | + | [[Category: Watson, K A.]] |
| - | [[Category: Zographos, S | + | [[Category: Zographos, S E.]] |
[[Category: GL7]] | [[Category: GL7]] | ||
[[Category: PLP]] | [[Category: PLP]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:42:35 2008'' |
Revision as of 10:42, 21 February 2008
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STRUCTURES OF GLYCOGEN PHOSPHORYLASE-INHIBITOR COMPLEXES AND THE IMPLICATIONS FOR STRUCTURE-BASED DRUG DESIGN
Overview
Glycogen phosphorylase (GP) is currently exploited as a target for inhibition of hepatic glycogenolysis under high glucose conditions. Spirohydantoin of glucopyranose and N-acetyl-beta-D-glucopyranosylamine have been identified as the most potent inhibitors of GP that bind at the catalytic site. Four spirohydantoin and three beta-D-glucopyranosylamine analogs have been designed, synthesized and tested for inhibition of GP in kinetic experiments. Depending on the functional group introduced, the K(i) values varied from 16.5 microM to 1200 microM. In order to rationalize the kinetic results, we determined the crystal structures of the analogs in complex with GP. All the inhibitors bound at the catalytic site of the enzyme, by making direct and water-mediated hydrogen bonds with the protein and by inducing minor movements of the side chains of Asp283 and Asn284, of the 280s loop that blocks access of the substrate glycogen to the catalytic site, and changes in the water structure in the vicinity of the site. The differences observed in the Ki values of the analogs can be interpreted in terms of variations in hydrogen bonding and van der Waals interactions, desolvation effects, ligand conformational entropy, and displacement of water molecules on ligand binding to the catalytic site.
About this Structure
1FTY is a Single protein structure of sequence from Oryctolagus cuniculus with and as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
Reference
Kinetic and crystallographic studies of glucopyranose spirohydantoin and glucopyranosylamine analogs inhibitors of glycogen phosphorylase., Watson KA, Chrysina ED, Tsitsanou KE, Zographos SE, Archontis G, Fleet GW, Oikonomakos NG, Proteins. 2005 Dec 1;61(4):966-83. PMID:16222658
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