5OX1

Glycogen Phosphorylase in complex with JLH270

Summary for 5OX1

• Entry DOI: 10.2210/pdb5ox1/pdb
• Related: 5OWY 5OWZ 5OX0
• Descriptor: Glycogen phosphorylase, muscle form, (2~{R},3~{S},4~{R},5~{R},6~{S})-2-(hydroxymethyl)-6-[5-(4-methoxyphenyl)-1~{H}-1,2,4-triazol-3-yl]oxane-3,4,5-triol, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: transferase
• Biological source: Oryctolagus cuniculus (Rabbit)
• Total number of polymer chains: 1
• Total formula weight: 98085.00

Authors

Kyriakis, E.,Stravodimos, G.A.,Kantsadi, A.L.,Chatzileontiadou, D.S.M.,Leonidas, D.D. (deposition date: 2017-09-05, release date: 2018-02-28)

Primary citation

Kyriakis, E.,Solovou, T.G.A.,Kun, S.,Czifrak, K.,Szocs, B.,Juhasz, L.,Bokor, E.,Stravodimos, G.A.,Kantsadi, A.L.,Chatzileontiadou, D.S.M.,Skamnaki, V.T.,Somsak, L.,Leonidas, D.D.
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.
Bioorg. Chem., 77:485-493, 2018

PubMed Abstract: Human 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 β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP. Here we probe the β-pocket by studying the inhibitory effect of six different groups at the para position of 3-(β-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 K value of 0.43 μM. Structural studies have revealed the physicochemical diversity of the β-pocket providing information for future rational inhibitor design studies.

PubMed: 29454281
DOI: 10.1016/j.bioorg.2018.02.008

Experimental method

X-RAY DIFFRACTION (1.85 Å)