1XC7

Binding of beta-D-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: Kinetic and crystallographic studies

Summary for 1XC7

• Entry DOI: 10.2210/pdb1xc7/pdb
• Related: 1K06 1P4G 1P4H 1P4J
• Descriptor: Glycogen phosphorylase, muscle form, N-(dimethoxyphosphoryl)-beta-D-glucopyranosylamine, SULFATE ION, ... (5 entities in total)
• Functional Keywords: glycogenolysis, type 2 diabetes, transferase
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 97921.61

Authors

Chrysina, E.D.,Kosmopoulou, M.N.,Kardakaris, R.,Bischler, N.,Leonidas, D.D.,Kannan, T.,Loganathan, D.,Oikonomakos, N.G. (deposition date: 2004-09-01, release date: 2005-02-08, Last modification date: 2025-03-26)

Primary citation

Chrysina, E.D.,Kosmopoulou, M.N.,Kardakaris, R.,Bischler, N.,Leonidas, D.D.,Kannan, T.,Loganathan, D.,Oikonomakos, N.G.
Binding of beta-d-glucopyranosyl bismethoxyphosphoramidate to glycogen phosphorylase b: kinetic and crystallographic studies
Bioorg.Med.Chem., 13:765-772, 2005

PubMed Abstract: In an attempt to identify a new lead molecule that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), beta-D-glucopyranosyl bismethoxyphosphoramidate (phosphoramidate), a glucosyl phosphate analogue, was tested for inhibition of the enzyme. Kinetic experiments showed that the compound was a weak competitive inhibitor of rabbit muscle GPb (with respect to alpha-D-glucose-1-phosphate (Glc-1-P)) with a Ki value of 5.9 (+/-0.1) mM. In order to elucidate the structural basis of inhibition, we determined the structure of GPb complexed with the phosphoramidate at 1.83 A resolution. The complex structure reveals that the inhibitor binds at the catalytic site and induces significant conformational changes in the vicinity of this site. In particular, the 280s loop (residues 282-287) shifts 0.4-4.3 A (main-chain atoms) to accommodate the phosphoramidate, but these conformational changes do not lead to increased contacts between the inhibitor and the protein that would improve ligand binding.

PubMed: 15653344
DOI: 10.1016/j.bmc.2004.10.040

Experimental method

X-RAY DIFFRACTION (1.83 Å)