1xc7
From Proteopedia
(New page: 200px<br /><applet load="1xc7" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xc7, resolution 1.83Å" /> '''Binding of beta-D-gl...) |
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| - | [[Image:1xc7.gif|left|200px]]<br /><applet load="1xc7" size=" | + | [[Image:1xc7.gif|left|200px]]<br /><applet load="1xc7" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1xc7, resolution 1.83Å" /> | caption="1xc7, resolution 1.83Å" /> | ||
'''Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: Kinetic and crystallographic studies'''<br /> | '''Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: Kinetic and crystallographic studies'''<br /> | ||
==Overview== | ==Overview== | ||
| - | In an attempt to identify a new lead molecule that would enable the design | + | In an attempt to identify a new lead molecule that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), beta-D-glucopyranosyl bismethoxyphosphoramidate (phosphoramidate), a glucosyl phosphate analogue, was tested for inhibition of the enzyme. Kinetic experiments showed that the compound was a weak competitive inhibitor of rabbit muscle GPb (with respect to alpha-D-glucose-1-phosphate (Glc-1-P)) with a Ki value of 5.9 (+/-0.1) mM. In order to elucidate the structural basis of inhibition, we determined the structure of GPb complexed with the phosphoramidate at 1.83 A resolution. The complex structure reveals that the inhibitor binds at the catalytic site and induces significant conformational changes in the vicinity of this site. In particular, the 280s loop (residues 282-287) shifts 0.4-4.3 A (main-chain atoms) to accommodate the phosphoramidate, but these conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding. |
==About this Structure== | ==About this Structure== | ||
| - | 1XC7 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 GL6, SO4 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:// | + | 1XC7 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=GL6:'>GL6</scene>, <scene name='pdbligand=SO4:'>SO4</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=1XC7 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bischler, N.]] | [[Category: Bischler, N.]] | ||
| - | [[Category: Chrysina, E | + | [[Category: Chrysina, E D.]] |
[[Category: Kannan, T.]] | [[Category: Kannan, T.]] | ||
[[Category: Kardakaris, R.]] | [[Category: Kardakaris, R.]] | ||
| - | [[Category: Kosmopoulou, M | + | [[Category: Kosmopoulou, M N.]] |
| - | [[Category: Leonidas, D | + | [[Category: Leonidas, D D.]] |
[[Category: Loganathan, D.]] | [[Category: Loganathan, D.]] | ||
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
[[Category: GL6]] | [[Category: GL6]] | ||
[[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 15:53:12 2008'' |
Revision as of 13:53, 21 February 2008
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Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: Kinetic and crystallographic studies
Overview
In an attempt to identify a new lead molecule that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), beta-D-glucopyranosyl bismethoxyphosphoramidate (phosphoramidate), a glucosyl phosphate analogue, was tested for inhibition of the enzyme. Kinetic experiments showed that the compound was a weak competitive inhibitor of rabbit muscle GPb (with respect to alpha-D-glucose-1-phosphate (Glc-1-P)) with a Ki value of 5.9 (+/-0.1) mM. In order to elucidate the structural basis of inhibition, we determined the structure of GPb complexed with the phosphoramidate at 1.83 A resolution. The complex structure reveals that the inhibitor binds at the catalytic site and induces significant conformational changes in the vicinity of this site. In particular, the 280s loop (residues 282-287) shifts 0.4-4.3 A (main-chain atoms) to accommodate the phosphoramidate, but these conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding.
About this Structure
1XC7 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
Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: kinetic and crystallographic studies., Chrysina ED, Kosmopoulou MN, Kardakaris R, Bischler N, Leonidas DD, Kannan T, Loganathan D, Oikonomakos NG, Bioorg Med Chem. 2005 Feb 1;13(3):765-72. PMID:15653344
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