1kti
From Proteopedia
(New page: 200px<br /><applet load="1kti" size="450" color="white" frame="true" align="right" spinBox="true" caption="1kti, resolution 1.97Å" /> '''BINDING OF 100 MM N-...) |
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| - | [[Image:1kti.gif|left|200px]]<br /><applet load="1kti" size=" | + | [[Image:1kti.gif|left|200px]]<br /><applet load="1kti" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1kti, resolution 1.97Å" /> | caption="1kti, resolution 1.97Å" /> | ||
'''BINDING OF 100 MM N-ACETYL-N'-BETA-D-GLUCOPYRANOSYL UREA TO GLYCOGEN PHOSPHORYLASE B: KINETIC AND CRYSTALLOGRAPHIC STUDIES'''<br /> | '''BINDING OF 100 MM N-ACETYL-N'-BETA-D-GLUCOPYRANOSYL UREA TO GLYCOGEN PHOSPHORYLASE B: KINETIC AND CRYSTALLOGRAPHIC STUDIES'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl | + | Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea (Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been identified as inhibitors of glycogen phosphorylase, a potential target for therapeutic intervention in type 2 diabetes. To elucidate the structural basis of inhibition, we determined the structure of muscle glycogen phosphorylase b (GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution, respectively. The structure of the GPb-Acurea complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change in the tertiary structure. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the acetyl urea moiety is in a favourable electrostatic environment and makes additional polar contacts with the protein. The structure of the GPb-Bzurea complex shows that Bzurea binds tightly at the catalytic site and induces substantial conformational changes in the vicinity of the catalytic site. In particular, the loop of the polypeptide chain containing residues 282-287 shifts 1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new allosteric site, some 33 A from the catalytic site, which is currently the target for the design of antidiabetic drugs. |
==About this Structure== | ==About this Structure== | ||
| - | 1KTI 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 AZC and PLP as [http://en.wikipedia.org/wiki/ligands ligands]. This structure | + | 1KTI 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=AZC:'>AZC</scene> and <scene name='pdbligand=PLP:'>PLP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. This structure supersedes the now removed PDB entry 1K0Q. 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=1KTI OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Phosphorylase]] | [[Category: Phosphorylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Chrysina, E | + | [[Category: Chrysina, E D.]] |
[[Category: Docsa, T.]] | [[Category: Docsa, T.]] | ||
[[Category: Gergely, P.]] | [[Category: Gergely, P.]] | ||
[[Category: Kosmopoulou, M.]] | [[Category: Kosmopoulou, M.]] | ||
| - | [[Category: Leonidas, D | + | [[Category: Leonidas, D D.]] |
[[Category: Nagy, V.]] | [[Category: Nagy, V.]] | ||
| - | [[Category: Oikonomakos, N | + | [[Category: Oikonomakos, N G.]] |
| - | [[Category: Praly, J | + | [[Category: Praly, J P.]] |
[[Category: Somsak, L.]] | [[Category: Somsak, L.]] | ||
[[Category: Toth, B.]] | [[Category: Toth, B.]] | ||
| - | [[Category: Zographos, S | + | [[Category: Zographos, S E.]] |
[[Category: AZC]] | [[Category: AZC]] | ||
[[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 13:37:45 2008'' |
Revision as of 11:37, 21 February 2008
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BINDING OF 100 MM N-ACETYL-N'-BETA-D-GLUCOPYRANOSYL UREA TO GLYCOGEN PHOSPHORYLASE B: KINETIC AND CRYSTALLOGRAPHIC STUDIES
Overview
Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea (Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been identified as inhibitors of glycogen phosphorylase, a potential target for therapeutic intervention in type 2 diabetes. To elucidate the structural basis of inhibition, we determined the structure of muscle glycogen phosphorylase b (GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution, respectively. The structure of the GPb-Acurea complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change in the tertiary structure. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the acetyl urea moiety is in a favourable electrostatic environment and makes additional polar contacts with the protein. The structure of the GPb-Bzurea complex shows that Bzurea binds tightly at the catalytic site and induces substantial conformational changes in the vicinity of the catalytic site. In particular, the loop of the polypeptide chain containing residues 282-287 shifts 1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new allosteric site, some 33 A from the catalytic site, which is currently the target for the design of antidiabetic drugs.
About this Structure
1KTI is a Single protein structure of sequence from Oryctolagus cuniculus with and as ligands. This structure supersedes the now removed PDB entry 1K0Q. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
Reference
Binding of N-acetyl-N '-beta-D-glucopyranosyl urea and N-benzoyl-N '-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies., Oikonomakos NG, Kosmopoulou M, Zographos SE, Leonidas DD, Chrysina ED, Somsak L, Nagy V, Praly JP, Docsa T, Toth B, Gergely P, Eur J Biochem. 2002 Mar;269(6):1684-96. PMID:11895439
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