Health & Environmental Research Online (HERO)


Print Feedback Export to File
1015682 
Journal Article 
Solution structure of Mycobacterium tuberculosis NmtR in the Apo state: Insights into Ni(II)-mediated allostery 
Lee, CW; Chakravorty, DK; Chang, F-MJ; Reyes-Caballero, H; Ye, Y; Merz, KM, Jr; Giedroc, DP 
In Press 
Yes 
Biochemistry
ISSN: 0006-2960
EISSN: 1520-4995 
51 
12 
2619-2629 
English 
Mycobacterium tuberculosis is an obligate human respiratory pathogen that encodes approximately 10 arsenic repressor (ArsR) family regulatory proteins that allow the organism to respond to a wide range of changes in its immediate microenvironment. How individual ArsR repressors have evolved to respond to selective stimuli is of intrinsic interest. The Ni(II)/Co(II)-specific repressor NmtR and related actinomycete nickel sensors harbor a conserved N-terminal α-NH(2)-Gly2-His3-Gly4 sequence. Here, we present the solution structure of homodimeric apo-NmtR and show that the core of the molecule adopts a typical winged-helix ArsR repressor (α1-α2-α3-αR-β1-β2-α5) "open conformation" that is similar to that of the related zinc sensor Staphylococcus aureus CzrA, but harboring long, flexible N-terminal (residues 2-16) and C-terminal (residues 109-120) extensions. Binding of Ni(II) to the regulatory sites induces strong paramagnetic broadening of the α5 helical region and the extreme N-terminal tail to residue 10. Ratiometric pulse chase amidination mass spectrometry reveals that the rate of amidination of the α-amino group of Gly2 is strongly attenuated in the Ni(II) complex relative to the apo state and noncognate Zn(II) complex. Ni(II) binding also induces dynamic disorder on the microsecond to millisecond time scale of key DNA interacting regions that likely contributes to the negative regulation of DNA binding by Ni(II). Molecular dynamics simulations and quantum chemical calculations reveal that NmtR readily accommodates a distal Ni(II) hexacoordination model involving the α-amine and His3 of the N-terminal region and α5 residues Asp91', His93', His104, and His107, which collectively define a new metal sensing site configuration in ArsR family regulators. 
IRIS
• Arsenic Hazard ID
     1. Initial Lit Search
          PubMed
          WOS
          WOS
          Considered New
     2. Lit Search Updates through Oct 2015
          WOS
          Considered
     4. Considered through Oct 2015
     6. Cluster Filter through Oct 2015
     7. Other Studies through Oct 2015
          Other
• Arsenic (Inorganic)
     1. Literature
          PubMed
          Web of Science
          Lit search updates through Oct 2015
     3. Hazard ID Screening
          Other potentially supporting studies
     4. Adverse Outcome Pathways/Networks Screening
          Excluded/Not relevant
               Title/Abstract screening
• Arsenic MOA
     1. MOA Literature Screening
          MOA Cluster
     3. Excluded
          Other not relevant
               Dragon Screened