2F3S

Crystal Structure of the glycogen phosphorylase B / ethyl-N-(beta-D-glucopyranosyl)oxamate complex

Summary for 2F3S

• Entry DOI: 10.2210/pdb2f3s/pdb
• Related: 2F3P 2F3Q 2F3U
• Descriptor: Glycogen phosphorylase, muscle form, PYRIDOXAL-5'-PHOSPHATE, N-[ethoxy(oxo)acetyl]-beta-D-glucopyranosylamine, ... (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: 97817.59

Authors

Oikonomakos, N.G.,Leonidas, D.D. (deposition date: 2005-11-22, release date: 2006-05-09, Last modification date: 2023-08-23)

Primary citation

Hadjiloi, T.,Tiraidis, C.,Chrysina, E.D.,Leonidas, D.D.,Oikonomakos, N.G.,Tsipos, P.,Gimisis, T.
Binding of oxalyl derivatives of beta-d-glucopyranosylamine to muscle glycogen phosphorylase b.
Bioorg.Med.Chem., 14:3872-3882, 2006

PubMed Abstract: Five oxalyl derivatives of beta-d-glucopyranosylamine were synthesized as potential inhibitors of glycogen phosphorylase (GP). The compounds 1-4 were competitive inhibitors of rabbit muscle GPb (with respect to alpha-d-glucose-1-phosphate) with K(i) values of 0.2-1.4 mM, while compound 5 was not effective up to a concentration of 10 mM. In order to elucidate the structural basis of their inhibition, we analysed the structures of compounds 1-4 in complex with GPb at 1.93-1.96 Angstrom resolution. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as alpha-d-glucose and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asp283 and Asn284 of this loop. Comparison with the lead compound N-acetyl-beta-d-glucopyranosylamine (6) shows that the hydrogen bonding interaction of the amide nitrogen with the main-chain carbonyl oxygen of His377 is not present in these complexes. The differences observed in the K(i) values of the four analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interactions, conformational entropy and desolvation effects.

PubMed: 16464598
DOI: 10.1016/j.bmc.2006.01.045

Experimental method

X-RAY DIFFRACTION (1.96 Å)