Peptidyl-tRNA Hydrolase

Peptidyl-tRNA is generated from stalled ribosomes. Peptidyl-tRNA hydrolase (Pth) enzymes are essential for the removal of bound peptides and recycling of tRNA. Peptidyl-tRNAs are toxic to cells and without Pth activity, cells die due to impaired translation initiation and slowed protein synthesis due to specific tRNA starvation. A majority of bacteria have one essential Pth enzyme, Pth1, making it a high value drug target. Disrupting Pth1 activity leads to bacterial death and since there is no essential Pth1 homolog found in humans, few side effects are expected from Pth1 inhibitors. We have solved the structure of the Pth1:peptidyl-tRNA complex using small-angle neutron scattering and are continuing with high resolution studies. We are screening natural products (tropical cloudforest and aquatic fungal extracts) expected to contain phytochemicals and secondary metabolites with novel structural motifs and novel mechanisms of bioactivity for Pth1 inhibitors. Numerous extracts have been identified with anti-Pth activity and identification of the active compound is in progress.

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Thought to be a novel eukaryotic Pth enzyme, this protein continues to defy classification.  Several new aspects of this proteins function have recently come to light, but a clear picture of its cellular role is still emerging.

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The carbohydrate binding protein Scytovirin has potent antiviral activity. The novel fold imparts specificity for Man4 carbohydrates found on coat glycoprotein of HIV, Ebola, Influenza, and Hepatitis. Biochemical and biophysical studies of the binding and bound complex have lead to structurally engineered mutants that have improved Man4 binding and anti-HIV efficacy. Current research goals are to systematically map mutations of amino acids known to be involved in carbohydrate binding, determine the effects of the number of binding sites on binding and efficacy (multivalency), characterize the structural stability of higher affinity mutants and correlate it to pharmacological activity/longevity, and solve the high-resolution structure of the carbohydrate bound complex.

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Site Specific Aromatic Labeling

Specific isotope labeling holds many advantages for NMR studies of macromolecular systems. We are developing Site Specific Aromatic Labeling (SSAL) to study ever larger systems and membrane proteins. The distinct chemical shifts of phenylalanine, tyrosine, and tryptophan side chains can be implemented as initiators in saturation transfer experiments and are readily distinguished in inter- and intramolecular NOE experiments. Successful production of 1H-13C phenylalanine has been established and recombinant protein expression shows >90% incorporation of phenylalanine. Optimization of SSAL phenylalanine expression is underway as well as production of tyrosine and tryptophan. The goal of this project is to make a widely applicable, inexpensive set of reagents to explore macromolecular structure/function/dynamics beyond current capabilities.

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