5ox1 | pdb_00005ox1
Glycogen Phosphorylase in complex with JLH270
Structural highlights
FunctionPYGM_RABIT Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMedHuman liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a beta-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the beta-pocket. Recently, C-beta-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the beta-pocket by studying the inhibitory effect of six different groups at the para position of 3-(beta-d-glucopyranosyl phenyl)-5-phenyl-, 1, 2, 4-triazoles in hlGP by kinetics and X-ray crystallography. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43muM. Structural studies have revealed the physicochemical diversity of the beta-pocket providing information for future rational inhibitor design studies. Probing the beta-pocket of the active site of human liver glycogen phosphorylase with 3-(C-beta-d-glucopyranosyl)-5-(4-substituted-phenyl)-1, 2, 4-triazole inhibitors.,Kyriakis E, Solovou TGA, Kun S, Czifrak K, Szocs B, Juhasz L, Bokor E, Stravodimos GA, Kantsadi AL, Chatzileontiadou DSM, Skamnaki VT, Somsak L, Leonidas DD Bioorg Chem. 2018 Feb 12;77:485-493. doi: 10.1016/j.bioorg.2018.02.008. PMID:29454281[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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