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<p>Abstract</p> <p>Background</p> <p>Analysis of the pathogen interactome is a powerful approach for dissecting potential signal transduction and virulence pathways. It also offers opportunities for exploring new drug targets.</p> <p>Results</p> <p>In this study, a protein-protein interaction (PPI) network of <it>Mycobacterium tuberculosis </it>H37Rv was constructed using a homogenous protein mapping method, which has shown molecular chaperones, ribosomal proteins and ABC transporters to be highly interconnected proteins. A further analysis of this network unraveled the function of hypothetical proteins as well as a potential signaling pathway. A hypothetical protein, Rv2752c, which was linked to a metal cation-transporting ATPase, was characterized as a metal-beta-lactamase, through domain analysis in combination with an <it>in vitro </it>activity experiment. A second hypothetical protein, Rv1354c, and an unknown protein kinase, PknK, interacted with a similar group of inner membrane-associated ABC transporters in the PPI network. The interactions of Rv1354 with these proteins were also confirmed by a further bacterial two-hybrid analysis. According to protein domain structures, the unique <it>M. tuberculosis </it>Rv1354c gene was proposed, for the first time, to be responsible for the turnover of cyclic-di-GMP, a second messenger molecule in this bacterium. A further structure-based inhibitors screening for Rv1354c was also performed <it>in silicon</it>.</p> <p>Conclusion</p> <p>We constructed a comprehensive protein-protein interaction network for <it>M. tuberculosis </it>consisting of 738 proteins and 5639 interaction pairs. Our analysis unraveled the function of hypothetical proteins as well as a potential signaling pathway. The group of ABC transporters, PknK, and Rv1354c were proposed to constitute a potential membrane-associated signaling pathway that cooperatively responds to environmental stresses in <it>M. tuberculosis</it>. The study therefore provides valuable clues in exploring new signaling proteins, virulence pathways, and drug targets.</p>