The importance of human glutathione synthetase (hGS) extends far beyond synthesis of the key antioxidant, glutathione, by providing a deeper understanding of allostery and ATP-grasp enzymes. An obligate dimer negatively cooperative towards its ?-glutamylcysteine subtrate, hGS provides an ideal model for both protein-protein interactions and allostery. Members of the ATP-grasp family of enzymes are involved in numerous of biosynthetic pathways; as one of the few mammalian ATP-grasp enzymes that has been structurally characterized, hGS offers insight into the function of these enzymes. This presentation focuses on utilizing molecular dynamics to explore the mode of allosteric communication and mechanism of substrate binding within hGS. Analysis of hydrogen bonds and shifts in global geometry within wild-type hGS and selected mutants served to probe the function of several residues and bonding states within hGS.  The computational analysis both complements and explains experimental studies, elucidating key aspects of hGS biochemistry. Supported by NIH R15GM086833.

Computational approach to understanding allostery in human glutathione synthetase

245th National Meeting (2013)

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