1UZU

Glycogen Phosphorylase b in complex with indirubin-5'-sulphonate

Summary for 1UZU

• Entry DOI: 10.2210/pdb1uzu/pdb
• Related: 1A8I 1ABB 1AXR 1B4D 1BX3 1C50 1C8K 1C8L 1E1Y 1FS4 1FTQ 1FTW 1FTY 1FU4 1FU7 1FU8 1GFZ 1GG8 1GGN 1GPA 1GPB 1GPY 1H5U 1HLF 1K06 1K08 1KTI 1LWN 1LWO 1NOI 1NOJ 1NOK 1P29 1P2B 1P2D 1P2G 1PYG 2AMV 2GPA 2GPB 2GPN 2PRI 2PRJ 2SKC 2SKD 2SKE 3AMV 3GPB 4GPB 5GPB 6GPB 7GPB 8GPB 9GPB
• Descriptor: GLYCOGEN PHOSPHORYLASE, MUSCLE FORM, PYRIDOXAL-5'-PHOSPHATE, 2',3-DIOXO-1,1',2',3-TETRAHYDRO-2,3'-BIINDOLE-5'-SULFONIC ACID, ... (4 entities in total)
• Functional Keywords: transferase, glycosyltransferase, glycogen metabolism, carbohydrate metabolism, pyridoxal phosphate
• Biological source: ORYCTOLAGUS CUNICULUS (RABBIT)
• Total number of polymer chains: 1
• Total formula weight: 97880.67

Authors

Kosmopoulou, M.N.,Leonidas, D.D.,Chrysina, E.D.,Bischler, N.,Eisenbrand, G.,Sakarellos, C.E.,Pauptit, R.,Oikonomakos, N.G. (deposition date: 2004-03-16, release date: 2004-05-27, Last modification date: 2023-12-13)

Primary citation

Kosmopoulou, M.N.,Leonidas, D.D.,Chrysina, E.D.,Bischler, N.,Eisenbrand, G.,Sakarellos, C.E.,Pauptit, R.,Oikonomakos, N.G.
Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Comparison with ligand binding to pCDK2-cyclin A complex.
Eur. J. Biochem., 271:2280-2290, 2004

PubMed Abstract: The binding of indirubin-5-sulphonate (E226), a potential anti-tumour agent and a potent inhibitor (IC(50) = 35 nm) of cyclin-dependent kinase 2 (CDK2) and glycogen phosphorylase (GP) has been studied by kinetic and crystallographic methods. Kinetic analysis revealed that E226 is a moderate inhibitor of GPb (K(i) = 13.8 +/- 0.2 micro m) and GPa (K(i) = 57.8 +/- 7.1 micro m) and acts synergistically with glucose. To explore the molecular basis of E226 binding we have determined the crystal structure of the GPb/E226 complex at 2.3 A resolution. Structure analysis shows clearly that E226 binds at the purine inhibitor site, where caffeine and flavopiridol also bind [Oikonomakos, N.G., Schnier, J.B., Zographos, S.E., Skamnaki, V.T., Tsitsanou, K.E. & Johnson, L.N. (2000) J. Biol. Chem.275, 34566-34573], by intercalating between the two aromatic rings of Phe285 and Tyr613. The mode of binding of E226 to GPb is similar, but not identical, to that of caffeine and flavopiridol. Comparative structural analyses of the GPb-E226, GPb-caffeine and GPb-flavopiridol complex structures reveal the structural basis of the differences in the potencies of the three inhibitors and indicate binding residues in the inhibitor site that can be exploited to obtain more potent inhibitors. Structural comparison of the GPb-E226 complex structure with the active pCDK2-cyclin A-E226 complex structure clearly shows the different binding modes of the ligand to GPb and CDK2; the more extensive interactions of E226 with the active site of CDK2 may explain its higher affinity towards the latter enzyme.

PubMed: 15153119
DOI: 10.1111/j.1432-1033.2004.04173.x

Experimental method

X-RAY DIFFRACTION (2.3 Å)