Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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HTH_DTXR Helix-turn-helix diphteria tox regulatory element

SMART accession number:	SM00529
Description:	iron dependent repressor
Interpro abstract (IPR022689):	The diphtheria toxin repressor protein (DTXR) is a member of this group [ (PUBMED:7568230) ]. In Corynebacterium diphtheriae where it has been studied in some detail this protein acts as an iron-binding repressor of dipheteria toxin gene expression and may serve as a global regulator of gene expression. DTXR comprises an N-terminal DNA-binding domain, an interface domain (which contains two metal-binding sites) and a third, very flexible C-terminal domain. The second domain is responsible for dimerization and metal binding. The N terminus may be involved in iron binding and may associate with the Tox operator. Binding of DTXR to Tox operator requires a divalent metal ion such as cobalt, ferric, manganese and nickel whereas zinc shows weak activation [ (PUBMED:7743135) ]. This entry represents a group of iron dependent repressors, including MntR, IdeR and diphtheria toxin repressor.
GO process:	regulation of transcription, DNA-templated (GO:0006355)
GO function:	transition metal ion binding (GO:0046914), DNA-binding transcription factor activity (GO:0003700)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 14037 HTH_DTXR domains in 14034 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing HTH_DTXR domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with HTH_DTXR domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing HTH_DTXR domain in the selected taxonomic class.

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Qiu X, Verlinde CL, Zhang S, Schmitt MP, Holmes RK, Hol WG
  • Three-dimensional structure of the diphtheria toxin repressor in complex with divalent cation co-repressors.
  • Structure. 1995; 3: 87-100
  • Display abstract

  • BACKGROUND: When Corynebacterium diphtheriae encounters an environment with a low concentration of iron ions, it initiates the synthesis of several virulence factors, including diphtheria toxin. The diphtheria toxin repressor (DtxR) plays a key role in this iron-dependent, global regulatory system and is the prototype for a new family of iron-dependent repressor proteins in Gram-positive bacteria. This study aimed to increase understanding of the general regulatory principles of cation binding to DtxR. RESULTS: The crystal structure of dimeric DtxR holo-repressor in complex with different transition metals shows that each subunit comprises an amino-terminal DNA-binding domain, an interface domain (which contains two metal-binding sites) and a third, very flexible carboxy-terminal domain. Each DNA-binding domain contains a helix-turn-helix motif and has a topology which is very similar to catabolite gene activator protein (CAP). Molecular modeling suggests that bound DNA adopts a bent conformation with helices alpha 3 of DtxR interacting with the major grooves. The two metal-binding sites lie approximately 10 A apart. Binding site 2 is positioned at a potential hinge region between the DNA-binding and interface domains. Residues 98-108 appear to be crucial for the functioning of the repressor; these provide four of the ligands of the two metal-binding sites and three residues at the other side of the helix which are at the heart of the dimer interface. CONCLUSIONS: The crystal structure of the DtxR holorepressor suggests that the divalent cation co-repressor controls motions of the DNA-binding domain. In this way the metal co-repressor governs the distance between operator recognition elements in the two subunits and, consequently, DNA recognition.

  • Schiering N, Tao X, Zeng H, Murphy JR, Petsko GA, Ringe D
  • Structures of the apo- and the metal ion-activated forms of the diphtheria tox repressor from Corynebacterium diphtheriae.
  • Proc Natl Acad Sci U S A. 1995; 92: 9843-50
  • Display abstract

  • The diphtheria tox repressor (DtxR) of Corynebacterium diphtheriae plays a critical role in the regulation of diphtheria toxin expression and the control of other iron-sensitive genes. The crystal structures of apo-DtxR and of the metal ion-activated form of the repressor have been solved and used to identify motifs involved in DNA and metal ion binding. Residues involved in binding of the activated repressor to the diphtheria tox operator, glutamine 43, arginine 47, and arginine 50, were located and confirmed by site-directed mutagenesis. Previous biochemical and genetic data can be explained in terms of these structures. Conformational differences between apo- and Ni-DtxR are discussed with regard to the mechanism of action of this repressor.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 100.00 map02010 ABC transporters - General This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with HTH_DTXR domain which could be assigned to a KEGG orthologous group, and not all proteins containing HTH_DTXR domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of HTH_DTXR domains in PDB

  PDB code	Main view	Title
  1b1b		IRON DEPENDENT REGULATOR
  1bi0		STRUCTURE OF APO-AND HOLO-DIPHTHERIA TOXIN REPRESSOR
  1bi1		STRUCTURE OF APO-AND HOLO-DIPHTHERIA TOXIN REPRESSOR
  1bi2		STRUCTURE OF APO-AND HOLO-DIPHTHERIA TOXIN REPRESSOR
  1bi3		STRUCTURE OF APO-AND HOLO-DIPHTHERIA TOXIN REPRESSOR
  1c0w		CRYSTAL STRUCTURE OF THE COBALT-ACTIVATED DIPHTHERIA TOXIN REPRESSOR-DNA COMPLEX REVEALS A METAL BINDING SH-LIKE DOMAIN
  1ddn		DIPHTHERIA TOX REPRESSOR (C102D MUTANT)/TOX DNA OPERATOR COMPLEX
  1dpr		STRUCTURES OF THE APO-AND METAL ION ACTIVATED FORMS OF THE DIPHTHERIA TOX REPRESSOR FROM CORYNEBACTERIUM DIPHTHERIAE
  1f5t		DIPHTHERIA TOX REPRESSOR (C102D MUTANT) COMPLEXED WITH NICKEL AND DTXR CONSENSUS BINDING SEQUENCE
  1fwz		GLU20ALA DTXR
  1fx7		CRYSTAL STRUCTURE OF THE IRON-DEPENDENT REGULATOR (IDER) FROM MYCOBACTERIUM TUBERCULOSIS
  1g3s		CYS102SER DTXR
  1g3t		CYS102SER DTXR
  1g3w		CD-CYS102SER DTXR
  1g3y		ARG80ALA DTXR
  1on1		Bacillus Subtilis Manganese Transport Regulator (Mntr) Bound To Manganese, AB Conformation.
  1on2		Bacillus subtilis Manganese Transport Regulator (MntR), D8M Mutant, Bound to Manganese
  1p92		Crystal Structure of (H79A)DtxR
  1u8r		Crystal Structure of an IdeR-DNA Complex Reveals a Conformational Change in Activated IdeR for Base-specific Interactions
  1xcv		Crystal Structure Of (H79AC102D)Dtxr complexed with Nickel(II)
  2dtr		STRUCTURE OF DIPHTHERIA TOXIN REPRESSOR
  2ev0		Bacillus subtilis manganese transport regulator (MNTR) bound to cadmium
  2ev5		Bacillus subtilis manganese transport regulator (MNTR) bound to calcium
  2ev6		Bacillus subtilis manganese transport regulator (MNTR) bound to zinc
  2f5c		Bacillus subtilis Manganese transport regulator (MNTR) bound to manganese, hexagonal crystal form
  2f5d		Bacillus subtilis manganese transport regulator (MNTR) bound to manganese, AC conformation, pH 6.5
  2f5e		Bacillus subtilis manganese transport regulator (MNTR) bound to manganese, AB conformation, pH 6.5
  2f5f		Bacillus subtilis manganese transport regulator (MNTR) bound to manganese, AC conformation, pH 8.5
  2h09		Crystal structure of diphtheria toxin repressor like protein from E. coli
  2hyf		The Structure of apo-MntR from Bacillus subtilis, selenomethionine derivative
  2hyg		The Structure of apo-MntR from Bacillus subtilis, Native Form
  2isy		Crystal structure of the nickel-activated two-domain iron-dependent regulator (IdeR)
  2isz		Crystal structure of a two-domain IdeR-DNA complex crystal form I
  2it0		Crystal structure of a two-domain IdeR-DNA complex crystal form II
  2qq9		Crystal Structure of DtxR(D6A C102D) Complexed with Nickel(II)
  2qqa		Crystal Structure of DtxR(E9A C102D) Complexed with Nickel(II)
  2qqb		Crystal Structure of DtxR(M10A C102D) Complexed with Nickel(II)
  2tdx		DIPHTHERIA TOX REPRESSOR (C102D MUTANT) COMPLEXED WITH NICKEL
  2x4h		Crystal Structure of the hypothetical protein SSo2273 from Sulfolobus solfataricus
  3glx		Crystal Structure Analysis of the DtxR(E175K) complexed with Ni(II)
  3hrs		Crystal Structure of the Manganese-activated Repressor ScaR: apo form
  3hrt		Crystal Structure of ScaR with bound Cd2+
  3hru		Crystal Structure of ScaR with bound Zn2+
  3r60		Structure of the MntR Fe2+ Complex
  3r61		Structure of the MntR Co2+ Complex
  4hv5		Structure of the MNTR FE2+ complex with E site metal binding
  4hv6		Structure of MNTR H77A mutant in apo- and mn-bound forms
  4hx4		Structure of MNTR mutant E11K complexed with Mn2+
  4hx7		Structure of MNTR E11K mutant complexed with Cd2+
  4hx8		Structure of metal-free MNTR mutant E11K
  4o5v		4O5V
  4o6j		Crystal sturucture of T. acidophilum IdeR
  5cvi		5CVI

• Links (links to other resources describing this domain)

• INTERPRO	IPR022689
  PFAM	Fe_dep_repress

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