1C8L

SYNERGISTIC INHIBITION OF GLYCOGEN PHOSPHORYLASE A BY A POTENTIAL ANTIDIABETIC DRUG AND CAFFEINE

Summary for 1C8L

• Entry DOI: 10.2210/pdb1c8l/pdb
• Descriptor: PROTEIN (GLYCOGEN PHOSPHORYLASE), PYRIDOXAL-5'-PHOSPHATE, 2,3-DICARBOXY-4-(2-CHLORO-PHENYL)-1-ETHYL-5-ISOPROPOXYCARBONYL-6-METHYL-PYRIDINIUM, ... (6 entities in total)
• Functional Keywords: glycogen metabolism, diabetes, phosphorylase a, synergistic inhibition, allosteric site, inhibitor site, transferase
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 1
• Total formula weight: 98311.44

Authors

Tsitsanou, K.E.,Skamnaki, V.T.,Oikonomakos, N.G. (deposition date: 2000-05-16, release date: 2000-05-31, Last modification date: 2023-08-09)

Primary citation

Tsitsanou, K.E.,Skamnaki, V.T.,Oikonomakos, N.G.
Structural basis of the synergistic inhibition of glycogen phosphorylase a by caffeine and a potential antidiabetic drug.
Arch.Biochem.Biophys., 384:245-254, 2000

PubMed Abstract: Caffeine, an allosteric inhibitor of glycogen phosphorylase a (GPa), has been shown to act synergistically with the potential antidiabetic drug (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarboxylate (W1807). The structure of GPa complexed with caffeine and W1807 has been determined at 100K to 2.3 A resolution, and refined to a crystallographic R value of 0.210 (Rfree = 0.257). The complex structure provides a rationale to understand the structural basis of the synergistic inhibition between W1807 and caffeine. W1807 binds tightly at the allosteric site, and induces substantial conformational changes both in the vicinity of the allosteric site and the subunit interface which transform GPa to the T'-like state conformation already observed with GPa-glucose-W1807 complex. A disordering of the N-terminal tail occurs, while the loop of polypeptide chain containing residues 192-196 and residues 43'-49', from the symmetry related subunit, shift to accommodate W1807. Caffeine binds at the purine inhibitor site by intercalating between the two aromatic rings of Phe285 and Tyr613 and stabilises the location of the 280s loop in the T state conformation.

PubMed: 11368311
DOI: 10.1006/abbi.2000.2121

Experimental method

X-RAY DIFFRACTION (2.3 Å)