1c8l: Difference between revisions
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'''SYNERGISTIC INHIBITION OF GLYCOGEN PHOSPHORYLASE A BY A POTENTIAL ANTIDIABETIC DRUG AND CAFFEINE''' | '''SYNERGISTIC INHIBITION OF GLYCOGEN PHOSPHORYLASE A BY A POTENTIAL ANTIDIABETIC DRUG AND CAFFEINE''' | ||
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[[Category: Skamnaki, V T.]] | [[Category: Skamnaki, V T.]] | ||
[[Category: Tsitsanou, K E.]] | [[Category: Tsitsanou, K E.]] | ||
[[Category: | [[Category: Allosteric site]] | ||
[[Category: | [[Category: Diabetes]] | ||
[[Category: | [[Category: Glycogen metabolism]] | ||
[[Category: | [[Category: Inhibitor site]] | ||
[[Category: | [[Category: Phosphorylase some]] | ||
[[Category: | [[Category: Synergistic inhibition]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 12:27:44 2008'' | |||
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Revision as of 12:27, 2 May 2008
SYNERGISTIC INHIBITION OF GLYCOGEN PHOSPHORYLASE A BY A POTENTIAL ANTIDIABETIC DRUG AND CAFFEINE
OverviewOverview
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 StructureAbout this Structure
1C8L is a Single protein structure of sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA.
ReferenceReference
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 Fri May 2 12:27:44 2008