1k06: Difference between revisions

Revision as of 14:28, 21 February 2008

Crystallographic Binding Study of 100 mM N-benzoyl-N'-beta-D-glucopyranosyl urea to glycogen phosphorylase b

OverviewOverview

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 StructureAbout this Structure

1K06 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 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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-[[Image:1k06.gif|left|200px]]<br /><applet load="1k06" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1k06.gif|left|200px]]<br /><applet load="1k06" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1k06, resolution 1.80&Aring;" />
 '''Crystallographic Binding Study of 100 mM N-benzoyl-N'-beta-D-glucopyranosyl urea to glycogen phosphorylase b'''<br />
 ==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.
+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==
-K06 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 BZD 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1K06 OCA].
+K06 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=BZD:'>BZD</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=1K06 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Phosphorylase]]
 [[Category: Single protein]]
-[[Category: Chrysina, E.D.]]
+[[Category: Chrysina, E D.]]
 [[Category: Docsa, T.]]
 [[Category: Gergely, P.]]
 [[Category: Kosmopoulou, M.]]
-[[Category: Leonidas, D.D.]]
+[[Category: Leonidas, D D.]]
 [[Category: Nagy, V.]]
-[[Category: Oikonomakos, N.G.]]
+[[Category: Oikonomakos, N G.]]
-[[Category: Praly, J.P.]]
+[[Category: Praly, J P.]]
 [[Category: Somsak, L.]]
 [[Category: Toth, B.]]
-[[Category: Zographos, S.E.]]
+[[Category: Zographos, S E.]]
 [[Category: BZD]]
 [[Category: PLP]]
@@ Line 32: / Line 32: @@
 [[Category: structure]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 18:44:27 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:28:39 2008''