2F3Q: Crystal Structure Of The Glycogen Phosphorylase B METHYL-N-(Beta-D- Glucopyranosyl)oxamate Complex

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.
PDB ID: 2F3QDownload
MMDB ID: 39238
PDB Deposition Date: 2005/11/22
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.96  Å
Source Organism:
Similar Structures:
Biological Unit for 2F3Q: dimeric; determined by author and by software (PISA,PQS)
Molecular Components in 2F3Q
Label Count Molecule
Proteins (2 molecules)
Glycogen Phosphorylase, Muscle Form(Gene symbol: PYGM)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

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