From Proteopedia

proteopedia linkproteopedia link

spinqualitylabelsall models 1ww3, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

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.

About this Structure

1WW3 is a Single protein structure of sequence from Oryctolagus cuniculus with NTF and PLP as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.

Reference

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

Page seeded by OCA on Wed Nov 21 05:42:36 2007