Structural diversity of HEPN domains. A member of each of the seven HEPN families with solved crystal structures is rendered as a cartoon; labels provide HEPN family name and PDB ID. Equivalent core helices are colored the same across all structures while labeled in the order observed from the N-terminus to the C-terminus to highlight circular permutations. In the canonical configuration, helix-1 (H1) and helix-2 (H2) from the first α-hairpin are colored green and blue, respectively and helix-3 (H3) and helix-4 (H4) from the second α-hairpin are colored cyan and yellow, respectively. The conserved insert region found between helix-2 and helix-3 in the canonical configuration is colored and labeled in light grey in each cartoon. The kink and further distortions are labeled in yellow. Conserved active site residues are rendered as ball and sticks and colored and labeled in red. Note the structural reorganization of HEPN domain in the Csx1 family. The distinctive β-hairpins of this family are colored and labeled in brown and the zinc ion found in the vicinity of the active site residues is rendered as a sphere and colored in purple.