Structure/function studies of information flow in M. tuberculosis

Texas A&M Agrilife Research, College Station TX

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Abstract

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