1c8l
From Proteopedia
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SYNERGISTIC INHIBITION OF GLYCOGEN PHOSPHORYLASE A BY A POTENTIAL ANTIDIABETIC DRUG AND CAFFEINE
Overview
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-tricarboxyl, ate (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.
About this Structure
1C8L is a Single protein structure of sequence from Oryctolagus cuniculus with PLP, BIN, CFF and GOL as ligands. Active as Phosphorylase, with EC number 2.4.1.1 Full crystallographic information is available from OCA.
Reference
Structural basis of the synergistic inhibition of glycogen phosphorylase a by caffeine and a potential antidiabetic drug., Tsitsanou KE, Skamnaki VT, Oikonomakos NG, Arch Biochem Biophys. 2000 Dec 15;384(2):245-54. PMID:11368311
Page seeded by OCA on Tue Nov 20 12:15:39 2007
