{PDOC50944}
{PS50944; HTH_DTXR}
{BEGIN}
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* DtxR-type HTH domain profile *
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The  dtxR-type  HTH  domain  is  a DNA-binding, winged helix-turn-helix (wHTH)
domain  of  about  65  residues  present in metalloregulators of the dtxR/mntR
family.  The  family  is  named  after  Corynebacterium  diphtheriae  dtxR, an
iron-specific  diphtheria  toxin  repressor,  and  Bacillus  subtilis  mntR, a
manganese  transport regulator. Iron-responsive metalloregulators such as dtxR
and  ideR  occur  in  Gram-positive  bacteria  of  the  high  GC branch, while
manganese-responsive  metalloregulators  like  mntR  are  described in diverse
genera  of  Gram-positive  and Gram-negative bacteria and also in Archaea [1].
The  metalloregulators  like  dtxR/mntR  contain the DNA-binding dtxR-type HTH
domain  usually  in  the  N-terminal  part.  The  C-terminal  part  contains a
dimerization  domain  with  two  metal-binding  sites,  although  the  primary
metal-binding    site    is   less   conserved   in   the   Mn(II)-regulators.
Fe(II)-regulated   proteins   contain  an  SH3-like  domain  as  a  C-terminal
extension, which is absent in Mn(II)-regulated mntR [2,3].

Metal-ion  dependent regulators orchestrate the virulence of several important
human pathogens. The dtxR protein regulates the expression of diphtheria toxin
in  response  to environmental iron concentrations. Furthermore, dtxR and ideR
control  iron  uptake  [4].  Homeostasis  of  manganese, which is an essential
nutrient, is regulated by mntR. A typical dtxR-type metalloregulator binds two
divalent metal effectors per monomer, upon which allosteric changes occur that
moderate binding to the cognate DNA operators. Iron-bound dtxR homodimers bind
to  an  interrupted  palindrome of 19 bp, protecting a sequence of ~30 bp. The
crystal  structures of iron-regulated (see <PDB:1C0W>) and manganese-regulated
(see  <PDB:1ON1>)  repressors  show that the DNA binding domain contains three
alpha-helices  and  a  pair  of  antiparallel  beta-strands.  Helices  2 and 3
comprise  the  helix-turn-helix motif and the beta-strands are called the wing
[3].  This  wHTH  topology  is similar to the lysR-type HTH (see <PDOC00043>).
Most dtxR-type metalloregulators bind as dimers to the DNA major groove.

Some proteins known to contain a dtxR-type HTH domain:

 - Corynebacterium  diphtheriae  dtxR,  a  diphtheria  toxin  repressor, which
   regulates  the  expression  of  the high-affinity iron uptake system, other
   iron-sensitive  genes,  and  the  bacteriophage  tox gene. Metal-bound dtxR
   represses  transcription  by binding the tox operator; if iron is limiting,
   conformational  changes  of the wHTH disrupt DNA-binding and the diphtheria
   toxin is produced.
 - Mycobacterium  tuberculosis  ideR,  an  iron-dependent  regulator  that  is
   essential  for  this  pathogen.  The  regulator  represses  genes  for iron
   acquisition  and  activates iron storage genes, and is a positive regulator
   of oxidative stress responses [4].
 - Bacillus  subtilis  mntR, a manganese transport regulator, binds Mn2+ as an
   effector  and is a transcriptional repressor of transporters for the import
   of manganese.
 - Treponema pallidum troR, a metal-dependent transcriptional repressor.
 - Archaeoglobus  fulgidus  MDR1  (troR),  a  metal-dependent  transcriptional
   repressor, which negatively regulates its own transcription.

The profile we developed covers the entire dtxR-type HTH domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: November 2003 / First entry.

[ 1] Guedon E., Helmann J.D.
     "Origins of metal ion selectivity in the DtxR/MntR family of
     metalloregulators."
     Mol. Microbiol. 48:495-506(2003).
     PubMed=12675807
[ 2] Spiering M.M., Ringe D., Murphy J.R., Marletta M.A.
     "Metal stoichiometry and functional studies of the diphtheria toxin
     repressor."
     Proc. Natl. Acad. Sci. U.S.A. 100:3808-3813(2003).
     PubMed=12655054; DOI=10.1073/pnas.0737977100
[ 3] Glasfeld A., Guedon E., Helmann J.D., Brennan R.G.
     "Structure of the manganese-bound manganese transport regulator of
     Bacillus subtilis."
     Nat. Struct. Biol. 10:652-657(2003).
     PubMed=12847518; DOI=10.1038/nsb951
[ 4] Rodriguez G.M., Smith I.
     "Mechanisms of iron regulation in mycobacteria: role in physiology and
     virulence."
     Mol. Microbiol. 47:1485-1494(2003).
     PubMed=12622807

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