Abstract
Memapsin 2 (beta-secretase) is a membrane-associated aspartic protease involved in the production of beta-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases
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Aspartic Acid Endopeptidases / chemistry*
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Aspartic Acid Endopeptidases / metabolism
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Catalytic Domain
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Crystallography, X-Ray
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Endopeptidases
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Humans
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Hydrogen Bonding
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Models, Molecular
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Oligopeptides / metabolism*
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Protease Inhibitors / chemistry
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Protease Inhibitors / metabolism*
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Protein Conformation
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Protein Folding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
Substances
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OM99-2
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Oligopeptides
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Protease Inhibitors
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Recombinant Proteins
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE2 protein, human
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BACE1 protein, human