<p>Bacterial transcription regulatory proteins that bind DNA via a helix-turn-helix (HTH) motif can be grouped into families on the basis of sequence similarities. One such group, termed arsR, includes several proteins that appear to dissociate from DNA in the presence of metal ions: arsR, which functions as a transcriptional repressor of an arsenic resistance operon; smtB from <taxon tax_id="1140">Synechococcus sp.</taxon> (strain PCC 7942), which acts as a transcriptional repressor of the smtA gene that codes for a metallothionein; cadC, a protein required for cadmium-resistance; and hypothetical protein yqcJ from <taxon tax_id="1423">Bacillus subtilis</taxon>.</p><p>The HTH motif is thought to be located in the central part of these proteins [<cite idref="PUB00004445"/>]. The motif is characterised by a number of well-conserved residues: at its N-terminal extremity is a cysteine residue; a second Cys is found in arsR and cadC, but not in smtA; and at the C terminus lie one or two histidines. These residues may be involved in metal-binding (Zn in smtB; metal-oxyanions such as arsenite, antimonite and arsenate for arsR; and cadmium for cadC) [<cite idref="PUB00004420"/>]. It is believed that binding of a metal ion could induce a conformational change that would prevent the protein from binding DNA [<cite idref="PUB00004420"/>].</p><p>The crystal structure of the cyanobacterial smtB shows a fold of fivealpha-helices (H) and a pair of antiparallel beta-strands (B) in the topologyH1-H2-H3-H4-B1-B2-H5. Helices 3 and 4 comprise thehelix-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 theDNA major groove. Most arsR/smtB-like metalloregulators form homodimers [<cite idref="PUB00015397"/>].The dimer interface is formed by helix 5 and an N-terminal part [<cite idref="PUB00003383"/>]. Twodistinct metal-binding sites have been identified. The first site comprisescysteine thiolates located in the HTH in helix 3 and for some cases in theN terminus, called the alpha3(N) site [<cite idref="PUB00004420"/>]. The second metal-binding siteis located in helix 5 (and C terminus) and is called the alpha5(C) site. Thealpha3N site binds large thiophilic, toxic metals including Cd, Pb, and Bi, asin S. aureus cadC. ArsR lacks the N-terminal arm and its alpha3 sitecoordinates smaller thiophilic ions like As and Sb. The alpha5 site containscarboxylate and imidazole ligands and interacts preferentially withbiologically required metal ions including Zn, Co, and Ni. ArsR-typemetalloregulators contain one of these sites, both, or other potentialmetal-binding sites [<cite idref="PUB00015398"/>, <cite idref="PUB00015399"/>]. Binding of metal ions to these sites leads toallosteric changes that can derepress the operator/promotor DNA. Themetal-inducible operons contain one or two imperfect 12-2-12 inverted repeats,which can be recognised by multimeric arsR-type metalloregulators.</p> Transcription regulator ArsR, conserved site