Structure of the Protease Domain of Memapsin 2 (β-Secretase) Complexed with Inhibitor

Abstract

Memapsin 2 (β-secretase) is a membrane-associated aspartic protease involved in the production of β-amyloid peptide in Alzheimer's disease and is a major target for drug design. We determined the crystal structure of the protease domain of human memapsin 2 complexed to an eight-residue inhibitor at 1.9 angstrom resolution. The active site of memapsin 2 is more open and less hydrophobic than that of other human aspartic proteases. The subsite locations from S ₄ to S ₂ ′ are well defined. A kink of the inhibitor chain at P ₂ ′ and the change of chain direction of P ₃ ′ and P ₄ ′ may be mimicked to provide inhibitor selectivity.