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

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Science  06 Oct 2000:
Vol. 290, Issue 5489, pp. 150-153
DOI: 10.1126/science.290.5489.150

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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 S4 to S2′ are well defined. A kink of the inhibitor chain at P2′ and the change of chain direction of P3′ and P4′ may be mimicked to provide inhibitor selectivity.

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