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

• HOME
• SETUP
• FAQ
• ABOUT
• GLOSSARY
• WHAT'S NEW
• FEEDBACK

HTH_ARSR helix_turn_helix, Arsenical Resistance Operon Repressor

SMART accession number:	SM00418
Description:	-
Interpro abstract (IPR001845):	The arsR-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain present in transcription regulators of the arsR/smtB family, involved in stress-response to heavy metal ions. This family of prokaryotic metal-sensing transcription repressors is named after Escherichia coli arsR, an arsenic-responsive repressor of the ars operon for arsenate reductase and metal ion extrusion, and after Synechococcus PCC 7942 smtB, a Zn(II)-responsive repressor of the smtA gene for a Zn sequestering metallothionein [ (PUBMED:12829264) ]. ArsR/smtB-like repressors of metal resistance operons specifically bind to the operator/promoter and seem to dissociate from the DNA in the presence of metal ions, permitting transcription of proteins involved in metal-ions efflux and/or detoxification. The crystal structure of the cyanobacterial smtB shows a fold of five alpha-helices (H) and a pair of antiparallel beta-strands (B) in the topology H1-H2-H3-H4-B1-B2-H5. Helices 3 and 4 comprise the helix-turn-helix motif and the beta-sheet is called the wing as in other wHTH, such as the dtxR-type or the merR-type. Helix 4 is termed the recognition helix, like in other HTHs where it binds the DNA major groove. Most arsR/smtB-like metalloregulators form homodimers [ (PUBMED:14568530) ]. The dimer interface is formed by helix 5 and an N-terminal part [ (PUBMED:9466913) ]. Two distinct metal-binding sites have been identified. The first site comprises cysteine thiolates located in the HTH in helix 3 and for some cases in the N terminus, called the alpha3(N) site [ (PUBMED:12829264) (PUBMED:14568530) (PUBMED:8506147) ]. The second metal-binding site is located in helix 5 (and C terminus) and is called the alpha5(C) site. The alpha3N site binds large thiophilic, toxic metals including Cd, Pb, and Bi, as in S. aureus cadC. ArsR lacks the N-terminal arm and its alpha3 site coordinates smaller thiophilic ions like As and Sb. The alpha5 site contains carboxylate and imidazole ligands and interacts preferentially with biologically required metal ions including Zn, Co, and Ni. ArsR-type metalloregulators contain one of these sites, both, or other potential metal-binding sites [ (PUBMED:12829264) (PUBMED:14960585) ]. Binding of metal ions to these sites leads to allosteric changes that can derepress the operator/promoter DNA. The metal-inducible operons contain one or two imperfect 12-2-12 inverted repeats, which can be recognised by multimeric arsR-type metalloregulators. Some proteins known to contain an arsR-type HTH domain: Escherichia coli arsR, an arsenic-responsive transcription repressor of the arsenic resistance operon (ars) which encodes an arsenate reductase and metal exporters. Synechococcus PCC 7942 smtB, a Zn(II)-responsive transcription repressor of the smtA gene that codes for a metallothionein. SmtB senses Co(II) and Cd(II) too, but Zn(II) is the preferred effector. Staphylococcus aureus cadC, a transcription regulator of the cadmium resistance (cad) operon which encodes a Cd/Pb-specific efflux ATPase [ (PUBMED:7543476) ]. Mycobacterium tuberculosis cmtR, a Pb(II)/Cd(II)-sensing repressor [ (PUBMED:15966722) ].
GO process:	regulation of transcription, DNA-templated (GO:0006355)
GO function:	DNA-binding transcription factor activity (GO:0003700)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 120969 HTH_ARSR domains in 120802 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_ARSR domain.

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

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

• Literature (relevant references for this domain)

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

  • Cook WJ, Kar SR, Taylor KB, Hall LM
  • Crystal structure of the cyanobacterial metallothionein repressor SmtB: a model for metalloregulatory proteins.
  • J Mol Biol. 1998; 275: 337-46
  • Display abstract

  • SmtB from Synechococcus PCC7942 is a trans-acting dimeric repressor that is required for Zn(2+)-responsive expression of the metallothionein SmtA. The structure of SmtB was solved using multiple isomorphous replacement techniques and refined at 2.2 A resolution by simulated annealing to an R-factor of 0.218. SmtB displays the classical helix-turn-helix motif found in many DNA-binding proteins. It has an alpha + beta topology, and the arrangement of the three core helices and the beta hairpin is similar to the HNF-3/fork head, CAP and diphtheria toxin repressor proteins. Although there is no zinc in the crystal structure, analysis of a mercuric acetate derivative suggests a total of four Zn2+ binding sites in the dimer. Two of these putative sites are at the opposite ends of the dimer, while the other two are at the dimer interface and are formed by residues contributed from each monomer. The structure of the dimer is such that simultaneous binding for both recognition helices to DNA would require either a bend in the DNA helix or a conformational change in the dimer. The structure of Synechococcus SmtB is the first in this family of metal-binding DNA repressors.

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

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 42.86 map00260 Glycine, serine and threonine metabolism 42.86 map00750 Vitamin B6 metabolism 14.29 map00780 Biotin metabolism 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_ARSR domain which could be assigned to a KEGG orthologous group, and not all proteins containing HTH_ARSR 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_ARSR domains in PDB

  PDB code	Main view	Title
  1r1t		Crystal structure of the cyanobacterial metallothionein repressor SmtB in the apo-form
  1r1u		Crystal structure of the metal-sensing transcriptional repressor CzrA from Staphylococcus aureus in the apo-form
  1r1v		Crystal structure of the metal-sensing transcriptional repressor CzrA from Staphylococcus aureus in the Zn2-form
  1r22		Crystal structure of the cyanobacterial metallothionein repressor SmtB (C14S/C61S/C121S mutant) in the Zn2alpha5-form
  1r23		Crystal structure of the cyanobacterial metallothionein repressor SmtB in the Zn1-form (one Zn(II) per dimer)
  1smt		SMTB REPRESSOR FROM SYNECHOCOCCUS PCC7942
  1u2w		Crystal Structure of the Staphylococcus aureus pI258 CadC
  1ub9		Structure of the transcriptional regulator homologue protein from Pyrococcus horikoshii OT3
  1uly		Crystal structure analysis of the ArsR homologue DNA-binding protein from P. horikoshii OT3
  2cwe		Crystal structure of hypothetical transcriptional regulator protein, PH1932 from Pyrococcus horikoshii OT3
  2jsc		NMR structure of the cadmium metal-sensor CMTR from Mycobacterium tuberculosis
  2kjb		Solution structure of CzrA in the DNA bound state
  2kjc		Solution structure of CzrA in the Zn(II) state
  2kko		Solution NMR structure of the homodimeric winged helix-turn-helix DNA-binding domain (fragment 1-100) Mb0332 from Mycobacterium bovis, a possible ArsR-family transcriptional regulator. Northeast Structural Genomics Consortium Target MbR242E.
  2lkp		solution structure of apo-NmtR
  2m30		Solution NMR refinement of a metal ion bound protein using quantum mechanical/molecular mechanical and molecular dynamics methods
  2oqg		ArsR-like Transcriptional Regulator from Rhodococcus sp. RHA1
  2p4w		Crystal structure of heat shock regulator from Pyrococcus furiosus
  2qlz		Crystal Structure of Transcription Factor PF0095 from Pyrococcus furiosus
  2quf		Crystal Structure of Transcription Factor AXXA-PF0095 from Pyrococcus furiosus
  2zkz		Crystal structure of the transcriptional repressor PagR of Bacillus anthracis
  3cuo		Crystal structure of the predicted DNA-binding transcriptional regulator from E. coli
  3f6o		Crystal structure of ArsR family transcriptional regulator, RHA00566
  3f6v		Crystal structure of Possible transcriptional regulator for arsenical resistance
  3f72		Crystal Structure of the Staphylococcus aureus pI258 CadC Metal Binding Site 2 Mutant
  3gw2		Crystal structure of possible transcriptional regulatory protein (fragment 1-100) from Mycobacterium bovis. Northeast Structural Genomics Consortium Target MbR242E.
  3jth		Crystal structure of a transcriptional regulator HlyU from Vibrio vulnificus CMCP6
  3pqj		Crystal Structure of the transcriptional repressor BigR from Xylella fastidiosa
  3pqk		Crystal Structure of the transcriptional repressor BigR from Xylella fastidiosa
  3tgn		Crystal Structure of the zinc-dependent MarR Family Transcriptional Regulator AdcR in the Zn(II)-bound State
  4ggg		Crystal structure of V66A/L68V CzrA in the Zn(II)bound state.
  4k2e		HlyU from Vibrio cholerae N16961
  4omy		Crystal Structure of SeMet NolR from Sinorhizobium fredii in complex with oligo AT DNA
  4omz		Crystal Structure of NolR from Sinorhizobium fredii
  4on0		Crystal Structure of NolR from Sinorhizobium fredii in complex with oligo AA DNA
  4ooi		4OOI
  4rs8		4RS8
  5k1y		5K1Y
  5k5o		5K5O
  5k5q		5K5Q
  5k5r		5K5R
  5kk1		5KK1

• Links (links to other resources describing this domain)

• PROSITE	HTH_ARSR_FAMILY
  PFAM	HTH_ARSR_family
  INTERPRO	IPR001845

Send comments to Ivica Letunic