1GGN

Structures of glycogen phosphorylase-inhibitor complexes and the implications for structure-based drug design

Summary for 1GGN

• Entry DOI: 10.2210/pdb1ggn/pdb
• Related: 1A8I
• Descriptor: PROTEIN (GLYCOGEN PHOSPHORYLASE), BETA-D-GLUCOPYRANOSE SPIROHYDANTOIN, PYRIDOXAL-5'-PHOSPHATE, ... (4 entities in total)
• Functional Keywords: transferase, glycogen phosphorylase, inhibitor complex, catalytic site, design
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 97786.54

Authors

Watson, K.A.,Tsitsanou, K.E.,Gregoriou, M.,Zographos, S.E.,Skamnaki, V.T.,Oikonomakos, N.G.,Fleet, G.W.,Johnson, L.N. (deposition date: 2000-08-29, release date: 2000-09-13, Last modification date: 2023-08-09)

Primary citation

Oikonomakos, N.G.,Skamnaki, V.T.,Osz, E.,Szilagyi, L.,Somsak, L.,Docsa, T.,Toth, B.,Gergely, P.
Kinetic and crystallographic studies of glucopyranosylidene spirothiohydantoin binding to glycogen phosphorylase B.
Bioorg.Med.Chem., 10:261-268, 2002

PubMed Abstract: Glucopyranosylidene spirothiohydantoin (TH) has been identified as a potential inhibitor of both muscle and liver glycogen phosphorylase b (GPb) and a (GPa) and shown to diminish liver GPa activity in vitro. Kinetic experiments reported here show that TH inhibits muscle GPb competitively with respect to both substrates phosphate (K(i)=2.3 microM) and glycogen (K(i)=2.8 microM). The structure of the GPb-TH complex has been determined at a resolution of 2.26 A and refined to a crystallographic R value of 0.193 (R(free)=0.211). The structure of GPb-TH complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provides a basis of understanding potency and specificity of the inhibitor. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the glucose complex, while the rigid thiohydantoin group is in a favourable electrostatic environment and makes additional polar contacts to the protein.

PubMed: 11741774
DOI: 10.1016/S0968-0896(01)00277-2

Experimental method

X-RAY DIFFRACTION (2.36 Å)