1XL1

Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1,3,4-oxadiazole,-benzothiazole, and-benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.

Summary for 1XL1

• Entry DOI: 10.2210/pdb1xl1/pdb
• Related: 1K06 1P4G 1P4H 1P4J 1XKX 1XL0
• Descriptor: Glycogen phosphorylase, muscle form, (1R)-1,5-anhydro-1-(5-methyl-1,3-benzothiazol-2-yl)-D-glucitol, PYRIDOXAL-5'-PHOSPHATE, ... (4 entities in total)
• Functional Keywords: glycogenolysis, type 2 diabetes, transferase
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 97849.70

Authors

Chrysina, E.D.,Kosmopoulou, M.N.,Tiraidis, C.,Kardakaris, R.,Bischler, N.,Leonidas, D.D.,Hadady, Z.,Somsak, L.,Docsa, T.,Gergely, P.,Oikonomakos, N.G. (deposition date: 2004-09-30, release date: 2005-03-15, Last modification date: 2020-07-29)

Primary citation

Chrysina, E.D.,Kosmopoulou, M.N.,Tiraidis, C.,Kardakaris, R.,Bischler, N.,Leonidas, D.D.,Hadady, Z.,Somsak, L.,Docsa, T.,Gergely, P.,Oikonomakos, N.G.
Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site
Protein Sci., 14:873-888, 2005

PubMed Abstract: In an attempt to identify leads that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), that might control hyperglycaemia in type 2 diabetes, three new analogs of beta-D-glucopyranose, 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole were assessed for their potency to inhibit GPb activity. The compounds showed competitive inhibition (with respect to substrate Glc-1-P) with K(i) values of 145.2 (+/-11.6), 76 (+/-4.8), and 8.6 (+/-0.7) muM, respectively. In order to establish the mechanism of this inhibition, crystallographic studies were carried out and the structures of GPb in complex with the three analogs were determined at high resolution (GPb-methyl-oxadiazole complex, 1.92 A; GPb-benzothiazole, 2.10 A; GPb-benzimidazole, 1.93 A). The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalization for understanding variations in potency of the inhibitors. In addition, benzimidazole bound at the new allosteric inhibitor or indole binding site, located at the subunit interface, in the region of the central cavity, and also at a novel binding site, located at the protein surface, far removed (approximately 32 A) from the other binding sites, that is mostly dominated by the nonpolar groups of Phe202, Tyr203, Val221, and Phe252.

PubMed: 15741340
DOI: 10.1110/ps.041216105

Experimental method

X-RAY DIFFRACTION (2.1 Å)