4MI3

Crystal structure of Gpb in complex with SUGAR (N-{(2R)-2-METHYL-3-[4-(PROPAN-2-YL)PHENYL]PROPANOYL}-BETA-D-GLUCOPYRANOSYLAMINE) (S21)

4MI3 の概要

• エントリーDOI: 10.2210/pdb4mi3/pdb
• 関連するPDBエントリー: 4MHO 4MHS 4MI6 4MI9 4MIC
• 分子名称: Glycogen phosphorylase, muscle form, N-{(2R)-2-methyl-3-[4-(propan-2-yl)phenyl]propanoyl}-beta-D-glucopyranosylamine (3 entities in total)
• 機能のキーワード: alpha and beta protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 95876.47

構造登録者

Kantsadi, L.A.,Chatzileontiadou, S.M.D.,Leonidas, D.D. (登録日: 2013-08-30, 公開日: 2014-07-23, 最終更新日: 2023-12-06)

主引用文献

Parmenopoulou, V.,Kantsadi, A.L.,Tsirkone, V.G.,Chatzileontiadou, D.S.,Manta, S.,Zographos, S.E.,Molfeta, C.,Archontis, G.,Agius, L.,Hayes, J.M.,Leonidas, D.D.,Komiotis, D.
Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-beta-d-glucopyranosylamines.
Bioorg.Med.Chem., 22:4810-4825, 2014

PubMed Abstract: Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-β-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a 'consensus scoring' approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants' values, in vitro, ranged from 5 to 377μM while two of them were effective at causing inactivation of GP in rat hepatocytes at low μM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors.

PubMed: 25092521
DOI: 10.1016/j.bmc.2014.06.058

実験手法

X-RAY DIFFRACTION (2.15 Å)