The canonical PX domain structure is composed of a three-stranded β-sheet (β1, β2 and β3) followed by three close-packed α-helices. The first and second α-helices are connected by an extended proline-rich sequence. Typically PX domains have been found to bind to the endosome-enriched lipid phosphatidylinositol-3-phosphate (PtdIns3P) via a basic pocket formed at the junction between the β3 strand, α1 helix and Pro-rich loop. In contrast SNX5, SNX6 and SNX32 possess major alterations in the PtdIns3P-binding pocket that preclude canonical lipid head-group docking (see below). In addition they possess a unique extended helix-turn-helix insert between the Pro-rich loop and α2 helix of unknown function (Figure 2B) (Koharudin et al., 2009).