HhH-GPD domain <p>Endonuclease III (<db_xref db="EC" dbkey="4.2.99.18"/>) is a DNA repair enzyme which removes a number of damaged pyrimidines from DNA via its glycosylase activity and also cleaves the phosphodiester backbone at apurinic / apyrimidinic sites via a beta-elimination mechanism [<cite idref="PUB00007293"/>, <cite idref="PUB00007294"/>]. The structurally related DNA glycosylase MutYrecognises and excises the mutational intermediate 8-oxoguanine-adenine mispair [<cite idref="PUB00002202"/>]. The 3-D structures of <taxon tax_id="562">Escherichia coli</taxon> endonuclease III [<cite idref="PUB00005158"/>] and catalytic domain of MutY [<cite idref="PUB00007295"/>] have been determined. Thestructures contain two all-alpha domains: a sequence-continuous, six-helix domain (residues 22-132) and a Greek-key,four-helix domain formed by one N-terminal and three C-terminal helices (residues 1-21 and 133-211) together with the[Fe4S4] cluster. The cluster is bound entirely within the C-terminal loop by four cysteine residues with a ligation patternCys-(Xaa)6-Cys-(Xaa)2-Cys-(Xaa)5-Cys which is distinct from all other known Fe4S4 proteins. This structural motif isreferred to as a [Fe4S4] cluster loop (FCL) [<cite idref="PUB00006161"/>]. Two DNA-binding motifs have been proposed, one at either end of theinterdomain groove: the helix-hairpin-helix (HhH) and FCL motifs (see <db_xref db="INTERPRO" dbkey="IPR003651"/>). The primary role of the iron-sulphur cluster appears toinvolve positioning conserved basic residues for interaction with the DNA phosphate backbone by forming the loop ofthe FCL motif [<cite idref="PUB00006161"/>, <cite idref="PUB00007296"/>]. </p><p>The HhH-GPD domain gets its name from its hallmark helix-hairpin-helix and Gly/Pro rich loop followed by a conserved aspartate. This domain is found in a diverse range of structurally related DNA repair proteins that include: endonuclease III, <db_xref db="EC" dbkey="4.2.99.18"/> and DNA glycosylase MutY, an A/G-specific adenine glycosylase. Both of these enzymes have a C-terminal iron-sulphur cluster loop (FCL). The methyl-CPG binding protein (MBD4) also contain a related domain that is a thymine DNA glycosylase. The family also includes DNA-3-methyladenine glycosylase II <db_xref db="EC" dbkey="3.2.2.21"/>, 8-oxoguanine DNA glycosylases and other members of the AlkA family.</p>