Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor

Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease invo lved in the production of beta-amyloid peptide in Alzheimer's disease and i s a major target for drug design. We determined the crystal structure of th e protease domain of human memapsin 2 complexed to an eight-residue inhibit or at 1.9 angstrom resolution. The active site of memapsin 2 is more open a nd less hydrophobic than that of other human aspartic proteases. The subsit e locations from S-4 to S-2' are well defined. A kink of the inhibitor chai n at P-2' and the change of chain direction of P-3' and P-4' may be mimicke d to provide inhibitor selectivity.