2f3p: Difference between revisions
New page: left|200px<br /><applet load="2f3p" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f3p, resolution 1.94Å" /> '''Crystal Structure of... |
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[[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size=" | [[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2f3p, resolution 1.94Å" /> | caption="2f3p, resolution 1.94Å" /> | ||
'''Crystal Structure of the glycogen phosphorylase B / N-(beta-D-glucopyranosyl)oxamic acid complex'''<br /> | '''Crystal Structure of the glycogen phosphorylase B / N-(beta-D-glucopyranosyl)oxamic acid complex'''<br /> | ||
==Overview== | ==Overview== | ||
Five oxalyl derivatives of beta-d-glucopyranosylamine were synthesized as | Five oxalyl derivatives of beta-d-glucopyranosylamine were synthesized as potential inhibitors of glycogen phosphorylase (GP). The compounds 1-4 were competitive inhibitors of rabbit muscle GPb (with respect to alpha-d-glucose-1-phosphate) with K(i) values of 0.2-1.4 mM, while compound 5 was not effective up to a concentration of 10 mM. In order to elucidate the structural basis of their inhibition, we analysed the structures of compounds 1-4 in complex with GPb at 1.93-1.96 Angstrom resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as alpha-d-glucose and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asp283 and Asn284 of this loop. Comparison with the lead compound N-acetyl-beta-d-glucopyranosylamine (6) shows that the hydrogen bonding interaction of the amide nitrogen with the main-chain carbonyl oxygen of His377 is not present in these complexes. The differences observed in the K(i) values of the four analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interactions, conformational entropy and desolvation effects. | ||
==About this Structure== | ==About this Structure== | ||
2F3P 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 and 4GP 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:// | 2F3P 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> and <scene name='pdbligand=4GP:'>4GP</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=2F3P OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Leonidas, D | [[Category: Leonidas, D D.]] | ||
[[Category: Oikonomakos, N | [[Category: Oikonomakos, N G.]] | ||
[[Category: 4GP]] | [[Category: 4GP]] | ||
[[Category: PLP]] | [[Category: PLP]] | ||
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[[Category: type 2 diabetes]] | [[Category: type 2 diabetes]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:22 2008'' | ||
Revision as of 18:17, 21 February 2008
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Crystal Structure of the glycogen phosphorylase B / N-(beta-D-glucopyranosyl)oxamic acid complex
OverviewOverview
Five oxalyl derivatives of beta-d-glucopyranosylamine were synthesized as potential inhibitors of glycogen phosphorylase (GP). The compounds 1-4 were competitive inhibitors of rabbit muscle GPb (with respect to alpha-d-glucose-1-phosphate) with K(i) values of 0.2-1.4 mM, while compound 5 was not effective up to a concentration of 10 mM. In order to elucidate the structural basis of their inhibition, we analysed the structures of compounds 1-4 in complex with GPb at 1.93-1.96 Angstrom resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as alpha-d-glucose and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asp283 and Asn284 of this loop. Comparison with the lead compound N-acetyl-beta-d-glucopyranosylamine (6) shows that the hydrogen bonding interaction of the amide nitrogen with the main-chain carbonyl oxygen of His377 is not present in these complexes. The differences observed in the K(i) values of the four analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interactions, conformational entropy and desolvation effects.
About this StructureAbout this Structure
2F3P 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.
ReferenceReference
Binding of oxalyl derivatives of beta-d-glucopyranosylamine to muscle glycogen phosphorylase b., Hadjiloi T, Tiraidis C, Chrysina ED, Leonidas DD, Oikonomakos NG, Tsipos P, Gimisis T, Bioorg Med Chem. 2006 Jun 1;14(11):3872-82. Epub 2006 Feb 7. PMID:16464598
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