STRUCTURAL INVESTIGATION OF LIGAND BINDING AND MECHANISM IN HUMAN GST OMEGA

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Omega class Glutathione-S-Transferases (GSTO) are the most recently discovered members of this structural family. They display several atypical activities of interest. Principally, that they are major enzymes involved in human arsenic metabolism. Due to consumption of contaminated drinking water, this is a process potentiating carcinogenesis and heart disease in millions of people worldwide. The details of how its toxicity is mediated however, are still poorly understood. Additionally, the Omega GSTs display dehydroascorbate and thioltransferase activities, the latter of which may play a role in modulating the function of other enzymes. Indeed, the Omega GSTs are implicated in Ryanodine Receptor modulation, the early development of Alzheimers and Parkinsons disease and are the target of pharmaceuticals that inhibit inteleukin-1b secretion. Of the two functional proteins belonging to this class, the first has proven most amenable to crystallization. Interestingly it posses an additional activity not shared by its homologue, the detoxification of pesticide metabolites to acetophenones. We wish to crystallographically characterize the mechanistic details of this enzyme in order to gain a more fundamental understanding of the physiological phenomena with which it is associated.