The long-term goal of this proposed collaborative project is to define the structural basis and mechanistic principles of systems that mediate information flow essential for virulence and persistence of Mycobacterium tuberculosis (Mtb). Within the framework of the TB Structural Genomics Consortium (TBSGC), we will focus structural, biochemical, computational, genetic and microarray methods on four processes?DMA replication and repair, transcription, phospho-Ser/Thr/Tyr signaling and sulfur metabolism. This research has four specific aims: 1. Define the structures and functions of Mtb proteins that mediate DMA replication and repair. 2. Determine the structures and mechanisms of inhibition of Mtb RNA polymerase, the Rho transcription termination factor and several RNases. 3. Determine the structures and signaling pathways of Ser/Thr kinases and protein tyrosine phosphatases in Mtb. 4. Establish the structures and the roles sulfotransfer enzymes in Mtb growth and persistence. The genomic perspective and broad attack needed to achieve these aims rest on strong collaborations with the other TBSGC components. The Core Facilities for Cloning and Protein Production will make many expression vectors and proteins for analysis. The crystallization core facilities will identify crystallization conditions, and the Data Collection Core will provide essential data for rapid structure determination. Microarray experiments in this project will help identify pathways and targets for all TBSGC components. Project 1 will use selected high-resolution structures for collaborative virtual screens for inhibitors. We will collaborate with the other Projects to analyze the structures and functions of key phosphorylated proteins. Coordination requires the TBSGC web site (Project 2) and administrative framework. This project and the TBSGC as a whole have high significance for human health. Mtb infects one third of the world's population and annually kills over two million people worldwide. By revealing how signals regulate Mtb metabolism and defining the mechanisms of antibiotic and inhibitor binding, this project will stimulate development of new therapeutics to efficiently cure persistent Mtb infections.
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