4EL5

Crystal structure of GPb in complex with DK12

Summary for 4EL5

• Entry DOI: 10.2210/pdb4el5/pdb
• Related: 4EJ2 4EKE 4EKY 4EL0
• Descriptor: Glycogen phosphorylase, muscle form, 5-ethynyl-1-(beta-D-glucopyranosyl)pyrimidine-2,4(1H,3H)-dione (3 entities in total)
• Functional Keywords: alpha/beta protein, transferase
• Biological source: Oryctolagus cuniculus (European rabbit,Japanese white rabbit,domestic rabbit,rabbits)
• Total number of polymer chains: 1
• Total formula weight: 95807.28

Authors

Kantsadi, A.L.,Skamnaki, V.T.,Leonidas, D.D. (deposition date: 2012-04-10, release date: 2012-07-25, Last modification date: 2023-12-06)

Primary citation

Kantsadi, A.L.,Manta, S.,Psarra, A.M.,Dimopoulou, A.,Kiritsis, C.,Parmenopoulou, V.,Skamnaki, V.T.,Zoumpoulakis, P.,Zographos, S.E.,Leonidas, D.D.,Komiotis, D.
The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: Synthesis, biochemical and biological assessment.
Eur.J.Med.Chem., 54:740-749, 2012

PubMed Abstract: C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides have been synthesized and studied as inhibitors of glycogen phosphorylase b (GPb). Kinetic experiments have shown that most of these compounds were low micromolar inhibitors of the enzyme. The best inhibitor was 1-(β-D-glucopyranosyl)-5-ethynyluracil (K(i)=4.7 μM). Crystallographic analysis of these compounds in complex with GPb revealed that inhibitors with a long C5-alkynyl group exploited interactions with β-pocket of the active site and induced significant conformational changes of the 280s loop compared to GPb in complex with compounds with a short C5-alkynyl group. The results highlight the importance in the length of the aliphatic groups used to enhance inhibitory potency for the exploitation of the hydrophobic β-pocket. The best of the inhibitors had also a moderate effect on glycogenolysis in the cellular lever with an IC(50) value of 291.4 μM.

PubMed: 22770609
DOI: 10.1016/j.ejmech.2012.06.029

Experimental method

X-RAY DIFFRACTION (2 Å)