2gwr
Crystal structure of the response regulator protein mtrA from Mycobacterium TuberculosisCrystal structure of the response regulator protein mtrA from Mycobacterium Tuberculosis
Structural highlights
FunctionMTRA_MYCTU Member of the two-component regulatory system MtrA/MtrB. Binds direct repeat motifs of sequence 5'-GTCACAGCG-3', phosphorylation confers higher affinity. Overexpression decreases bacteria viability upon infection of human THP-1 macrophage cell line, due at least in part to impaired blockage of phagosome-lysosome fusion (upon infection bacteria usually remain in phagosomes). Infecting C57BL/6 mice with an overexpressing strain leads to an attentuated infection in both spleen and lungs. The level of dnaA mRNA increases dramatically. Binds the promoter of dnaA, fbpD, ripA and itself, as well as oriC, which it may regulate. Upon co-overexpression of MrtA and MtrB growth in macrophages is partially restored, dnaA expression is not induced, although mouse infections are still attenuated, suggesting that bacterial growth in macrophages requires an optimal ratio of MtrB to MtrA.[1] [2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe structure of MtrA, an essential gene product for the human pathogen Mycobacterium tuberculosis, has been solved to a resolution of 2.1 A. MtrA is a member of the OmpR/PhoB family of response regulators and represents the fourth family member for which a structure of the protein in its inactive state has been determined. As is true for all OmpR/PhoB family members, MtrA possesses an N-terminal regulatory domain and a C-terminal winged helix-turn-helix DNA-binding domain, with phosphorylation of the regulatory domain modulating the activity of the protein. In the inactive form of MtrA, these two domains form an extensive interface that is composed of the alpha4-beta5-alpha5 face of the regulatory domain and the C-terminal end of the positioning helix, the trans-activation loop, and the recognition helix of the DNA-binding domain. This domain orientation suggests a mechanism of mutual inhibition by the two domains. Activation of MtrA would require a disruption of this interface to allow the alpha4-beta5-alpha5 face of the regulatory domain to form the intermolecule interactions that are associated with the active state and to allow the recognition helix to interact with DNA. Furthermore, the interface appears to stabilize the inactive conformation of MtrA, potentially reducing the rate of phosphorylation of the N-terminal domain. This combination of effects may form a switch, regulating the activity of MtrA. The domain orientation exhibited by MtrA also provides a rationale for the variation in linker length that is observed within the OmpR/PhoB family of response regulators. Domain orientation in the inactive response regulator Mycobacterium tuberculosis MtrA provides a barrier to activation.,Friedland N, Mack TR, Yu M, Hung LW, Terwilliger TC, Waldo GS, Stock AM Biochemistry. 2007 Jun 12;46(23):6733-43. Epub 2007 May 19. PMID:17511470[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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