The crystal structures of complexes of the aspartic proteinases, human and mouse renins, yeast proteinase A and cathepsin D, with peptide analogue inhibitors are compared. Differences occur in the relative positions of the domain comprising residues 190-302 (pepsin numbering) compared to the remaining structure and in the nature and position of the irregular regions joining the β-strands and α-helices. The first three of the five residues of the oligosaccharide structures attached to Asn 67 of yeast proteinase and cathepsin D cover the same region of the protein surface. All enzymes have an unusual, proline-rich region (292-297) which acts as a second flap (in addition to that involving residues 72-81). This covers the active site cleft, but can be very close to the substrate/inhibitor at P3' and P4' only in the renins.