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

• DOI: 10.1126/science.290.5489.150
• Publication Date: 2002-07-27T09:53:24Z
• Authors: Lin Hong; Gerald Koelsch; Xinli Lin; Shili Wu; Simon Terzyan; Arun K. Ghosh; Xuenjun C. Zhang; Jordan Tang
• Keywords: Models, Molecular; 0301 basic medicine; Protein Folding; Protein Conformation; Hydrogen Bonding; Crystallography, X-Ray; Protein Structure, Secondary; Recombinant Proteins; Protein Structure, Tertiary; 3. Good health; 03 medical and health sciences; Catalytic Domain; Endopeptidases; Aspartic Acid Endopeptidases; Humans; Protease Inhibitors; Amyloid Precursor Protein Secretases; Oligopeptides

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.