Structural basis of the synergistic inhibition of glycogen phosphorylase aby caffeine and a potential antidiabetic drug

Caffeine, an allosteric inhibitor of glycogen phosphorylase a (GPa), has be en 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 W1 807 has been determined at 100K to 2.3 Angstrom resolution, and refined to a crystallographic R value of 0.210 (R-free = 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 alloster ic site, and induces substantial conformational changes both in the vicinit y of the allosteric site and the subunit interface which transform GPa to t he T'-like state conformation already observed with GPa- glucose-W1807 comp lex. A disordering of the N-terminal tail occurs, while the loop of polypep tide chain containing residues 192-196 and residues 43'-49', from the symme try related sub unit, shift to accommodate W1807, Caffeine binds at the pur ine inhibitor site by intercalating between the two aromatic rings of Phe28 5 and Tyr613 and stabilises the location of the 280s loop in the T state co nformation, (C) 2000 Academic Press.