2amv
From Proteopedia
(New page: 200px<br /><applet load="2amv" size="450" color="white" frame="true" align="right" spinBox="true" caption="2amv, resolution 2.3Å" /> '''THE STRUCTURE OF GLYC...) |
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| - | [[Image:2amv.gif|left|200px]]<br /><applet load="2amv" size=" | + | [[Image:2amv.gif|left|200px]]<br /><applet load="2amv" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2amv, resolution 2.3Å" /> | caption="2amv, resolution 2.3Å" /> | ||
'''THE STRUCTURE OF GLYCOGEN PHOSPHORYLASE B WITH AN ALKYL-DIHYDROPYRIDINE-DICARBOXYLIC ACID'''<br /> | '''THE STRUCTURE OF GLYCOGEN PHOSPHORYLASE B WITH AN ALKYL-DIHYDROPYRIDINE-DICARBOXYLIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: In muscle and liver, glycogen concentrations are regulated by | + | BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor of GP, and as such has potential to contribute to the regulation of glycogen metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor has no structural similarity to the natural regulators of GP. We have carried out structural studies in order to elucidate the mechanism of inhibition. RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show that the compound (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate (Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to AMP. The structure of the cocrystallised GPb-W1807 complex has been determined at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287). W1807 binds at the GPb allosteric effector site, the site which binds AMP, glucose-6-phosphate and a number of other phosphorylated ligands, and induces conformational changes that are characteristic of those observed with the naturally occurring allosteric inhibitor, glucose-6-phosphate. The dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands that bind to the allosteric site and contact three arginine residues. CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the numerous nonpolar interactions made between the ligand and the protein. Its potency as an inhibitor results from the induced conformational changes that lock the enzyme in a conformation known as the T' state. Allosteric enzymes, such as GP, offer a new strategy for structure-based drug design in which the allosteric site can be exploited. The results reported here may have important implications in the design of new therapeutic compounds. |
==About this Structure== | ==About this Structure== | ||
| - | 2AMV 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 PLP, BIN and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 2AMV 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=PLP:'>PLP</scene>, <scene name='pdbligand=BIN:'>BIN</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1AMV. 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=2AMV OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Johnson, L | + | [[Category: Johnson, L N.]] |
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
| - | [[Category: Zographos, S | + | [[Category: Zographos, S E.]] |
[[Category: BIN]] | [[Category: BIN]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: inhibitors]] | [[Category: inhibitors]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:28:54 2008'' |
Revision as of 14:28, 21 February 2008
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THE STRUCTURE OF GLYCOGEN PHOSPHORYLASE B WITH AN ALKYL-DIHYDROPYRIDINE-DICARBOXYLIC ACID
Overview
BACKGROUND: In muscle and liver, glycogen concentrations are regulated by the reciprocal activities of glycogen phosphorylase (GP) and glycogen synthase. An alkyl-dihydropyridine-dicarboxylic acid has been found to be a potent inhibitor of GP, and as such has potential to contribute to the regulation of glycogen metabolism in the non-insulin-dependent diabetes diseased state. The inhibitor has no structural similarity to the natural regulators of GP. We have carried out structural studies in order to elucidate the mechanism of inhibition. RESULTS: Kinetic studies with rabbit muscle glycogen phosphorylase b (GPb) show that the compound (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5, 6-tricarboxylate (Bay W1807) has a Ki = 1.6 nM and is a competitive inhibitor with respect to AMP. The structure of the cocrystallised GPb-W1807 complex has been determined at 100K to 2.3 A resolution and refined to an R factor of 0.198 (Rfree = 0.287). W1807 binds at the GPb allosteric effector site, the site which binds AMP, glucose-6-phosphate and a number of other phosphorylated ligands, and induces conformational changes that are characteristic of those observed with the naturally occurring allosteric inhibitor, glucose-6-phosphate. The dihydropyridine-5,6-dicarboxylate groups mimic the phosphate group of ligands that bind to the allosteric site and contact three arginine residues. CONCLUSIONS: The high affinity of W1807 for GP appears to arise from the numerous nonpolar interactions made between the ligand and the protein. Its potency as an inhibitor results from the induced conformational changes that lock the enzyme in a conformation known as the T' state. Allosteric enzymes, such as GP, offer a new strategy for structure-based drug design in which the allosteric site can be exploited. The results reported here may have important implications in the design of new therapeutic compounds.
About this Structure
2AMV is a Single protein structure of sequence from Oryctolagus cuniculus with , and as ligands. This structure supersedes the now removed PDB entry 1AMV. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
Reference
The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor., Zographos SE, Oikonomakos NG, Tsitsanou KE, Leonidas DD, Chrysina ED, Skamnaki VT, Bischoff H, Goldmann S, Watson KA, Johnson LN, Structure. 1997 Nov 15;5(11):1413-25. PMID:9384557
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