Project abstract for group thompson

Iron-Sulfur Cluster Biogenesis and Structure-Based Drug Design

This group is involved in two projects that use MSI.

The first concerns iron-sulfur cluster biogenesis. Iron sulfur clusters (ISCs) are co-factors with known functions in the Kreb’s cycle, electron transport chain, DNA synthesis and repair and as regulators for iron homeostasis. The current paradigm is that Isu1 protein acts as a shuttle between the iron donor (Yfh1) and sulfur donor (Nfs1). In contrast, the group's hypothesis is that several proteins form a stable complex in which ISCs are formed, so toxic iron and sulfur can be transported safely to scaffold proteins in addition to the safe transfer of oxygen-sensitive clusters to apo-enzymes. To investigate the structure and function of ISCs complex proteins, they are beginning to describe the structure of the yeast ISC protein complex consisting of Yfh1, Isu1 and Nfs1, in part, by small-angle X-ray scattering (SAXS). They use MSI resources to model SAXS data in hand. This work will aid understanding of normal physiologic processes such as aging, but just as importantly, many pathological conditions, which include Freidreich’s ataxia, Huntington’s, Parkinson’s, Alzheimer’s, and cancer.

The second project involves structure-based drug design. Evidence suggests changes in oligomerization of the abundant dihydrolipoamide dehydrogenase (DLD) results in a significant, yet unappreciated, source of disease symptoms including iron imbalance and oxidative stress. DLD is an essential contributor to mitochondrial energy metabolism. Surprisingly, physiological dimers break into monomers exposing “moonlighting” activities that degrade vital mitochondrial proteins and increase oxidative stress. This project's hypothesis is that stabilizing dimeric DLD will decrease these proteolytic and diaphorase activities of monomeric DLD. The researchers are designing/optimizing compounds with this function to explore DLD's role in aging and several diseases involving iron imbalance and oxidative stress. MSI resources permit an increase in docking computations performed.