2f3p: Difference between revisions

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[[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size="350" color="white" frame="true" align="right" spinBox="true"

caption="2f3p, resolution 1.94Å" />

'''Crystal Structure of the glycogen phosphorylase B / N-(beta-D-glucopyranosyl)oxamic acid complex'''<br />

==Overview==

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.

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==

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://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2F3P OCA].

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==

Line 14:

[[Category: Phosphorylase]]

[[Category: Single protein]]

[[Category: Leonidas, D.D.]]

[[Category: Leonidas, D D.]]

[[Category: Oikonomakos, N.G.]]

[[Category: Oikonomakos, N G.]]

[[Category: 4GP]]

[[Category: PLP]]

Line 21:

[[Category: type 2 diabetes]]

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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:22 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2f3p.gif|left|200px]]<br /><applet load="2f3p" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2f3p, resolution 1.94&Aring;" />
 '''Crystal Structure of the glycogen phosphorylase B / N-(beta-D-glucopyranosyl)oxamic acid complex'''<br />
 ==Overview==
-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.
+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==
-F3P 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=2F3P OCA].
+F3P 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==
@@ Line 14: / Line 14: @@
 [[Category: Phosphorylase]]
 [[Category: Single protein]]
-[[Category: Leonidas, D.D.]]
+[[Category: Leonidas, D D.]]
-[[Category: Oikonomakos, N.G.]]
+[[Category: Oikonomakos, N G.]]
 [[Category: 4GP]]
 [[Category: PLP]]
@@ Line 21: / Line 21: @@
 [[Category: type 2 diabetes]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 10:20:37 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:17:22 2008''