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| - Disorder-to-Order Transition of the Active Site of Human Class Pi GlutathioneTransferase, GST P1-1
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| - Glutathione transferases comprise a large family of cellular detoxification enzymes that functionby catalyzing the conjugation of glutathione (GSH) to electron-deficient centers on carcinogens and othertoxins. NMR methods have been used to characterize the structure and dynamics of a human class pienzyme, GST P1-1, in solution. Resonance assignments have been obtained for the unliganded enzymeand the GSH and S-hexylglutathione (GS-hexyl) complexes. Differences in chemical shifts between theGSH and GS-hexyl complexes suggest more extensive structural differences between these two enzyme−ligand complexes than detected by previous crystallographic methods. The NMR studies reported hereclearly show that an α-helix (α2) within the GSH binding site exists in multiple conformations atphysiological temperatures in the absence of ligand. A single conformation of α2 is induced by the presenceof either GSH or GS-hexyl or a reduction in temperature to below 290 K. The large enthalpy of thetransition (∼150 kJ/mol) suggests a considerable structural rearrangement of the protein. The Gibbs freeenergy for the transition to the unfolded form is on the order of −4 to −6 kJ/mol at physiologicaltemperatures (37 °C). This order-to-disorder transition contributes substantially to the overall thermodynamics of ligand binding and should be considered in the design of selective inhibitors of class pi glutathionetransferases.
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