1ww3: Difference between revisions

Revision as of 16:48, 21 February 2008

Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase

OverviewOverview

Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (K(i) = 32 microM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 angstroms resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K(i) = 75 microM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 angstroms resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb-NAG complex at a higher resolution (1.9 angstroms). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the K(i) values of the two 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 interaction, and desolvation effects.

About this StructureAbout this Structure

1WW3 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

Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase., Anagnostou E, Kosmopoulou MN, Chrysina ED, Leonidas DD, Hadjiloi T, Tiraidis C, Zographos SE, Gyorgydeak Z, Somsak L, Docsa T, Gergely P, Kolisis FN, Oikonomakos NG, Bioorg Med Chem. 2006 Jan 1;14(1):181-9. Epub 2005 Oct 4. PMID:16213146

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-[[Image:1ww3.gif|left|200px]]<br /><applet load="1ww3" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1ww3.gif|left|200px]]<br /><applet load="1ww3" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1ww3, resolution 1.80&Aring;" />
 '''Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase'''<br />
 ==Overview==
-Structure-based inhibitor design has led to the discovery of a number of, potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of, beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme., The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (K(i) = 32 microM), has been, previously characterized by biochemical, biological and crystallographic, experiments at 2.3 angstroms resolution. Bioisosteric replacement of the, acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K(i) = 75, microM. To elucidate the structural basis of its reduced potency, we, determined the ligand structure in complex with GPb at 1.8 angstroms, resolution. To compare the binding mode of N-trifluoroacetyl derivative, with that of the lead molecule, we also determined the structure of, GPb-NAG complex at a higher resolution (1.9 angstroms). NFAG can be, accommodated in the catalytic site of T-state GPb at approximately the, same position as that of NAG and stabilize the T-state conformation of the, 280 s loop by making several favourable contacts to Asn284 of this loop., The difference observed in the K(i) values of the two 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 interaction, and desolvation effects.
+Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (K(i) = 32 microM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 angstroms resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K(i) = 75 microM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 angstroms resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb-NAG complex at a higher resolution (1.9 angstroms). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the K(i) values of the two 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 interaction, and desolvation effects.
 ==About this Structure==
-WW3 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 NTF 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=1WW3 OCA].
+WW3 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=NTF:'>NTF</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=1WW3 OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Anagnostou, E.]]
-[[Category: Chrysina, E.D.]]
+[[Category: Chrysina, E D.]]
 [[Category: Docsa, T.]]
 [[Category: Gergely, P.]]
 [[Category: Gyorgydeak, Z.]]
 [[Category: Hadjiloi, T.]]
-[[Category: Kolisis, F.N.]]
+[[Category: Kolisis, F N.]]
-[[Category: Kosmopoulou, M.N.]]
+[[Category: Kosmopoulou, M N.]]
-[[Category: Leonidas, D.D.]]
+[[Category: Leonidas, D D.]]
-[[Category: Oikonomakos, N.G.]]
+[[Category: Oikonomakos, N G.]]
 [[Category: Somsak, L.]]
 [[Category: Tiraidis, C.]]
-[[Category: Zographos, S.E.]]
+[[Category: Zographos, S E.]]
 [[Category: NTF]]
 [[Category: PLP]]
@@ Line 32: / Line 32: @@
 [[Category: type 2 diabetes]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 05:42:36 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:48:42 2008''