A new essential protein kinase in Mycobacterium tuberculosis

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 DESCRIPTION (provided by applicant) Phosphosignaling controls Mycobacterium tuberculosis (Mtb) physiology and pathogenesis on every level. In addition to two-component systems that phosphorylate protein on His and Asp, Mtb also produces eleven Ser/Thr kinases (STPKs). These STPKs are central for bacterial adaptations, and two Mtb STPKs, PknA and PknB, are essential for growth and under development as drug targets. The eleven STPKs were identified in the 1998 Mtb genome sequence, and no new STPKs have been described since. In a functional proteomics screen of Mtb ATPases, we identified >80 hypothetical proteins as novel, previously unrecognized ATPases. Further characterization showed remote structural homology of one of the hypotheticals, Rv0647c, with non- typical STPKs. Given the ATPase activity of Rv0647c, we tested for STPK activity and found that Rv0647c is a novel, highly divergent STPK. Importantly, Rv0647c is predicted to be essential, suggesting that Rv0647c has central functions relating to Mtb growth. Here, we will test the hypothesis that Rv0647c is a growth regulator kinase in Mtb by testing Rv0647c's essentiality, identifying cellular substrates, and by solving the Rv0647c crystal structure. Together, this project identifies a new component of the Mtb phosphosignaling network and provides the basis for targeting this member of a highly druggable enzyme family.