Jm. Sauder et al., Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase, J MOL BIOL, 300(2), 2000, pp. 241-248
The enzyme BACE (beta-site APP-cleaving enzyme) has recently been identifie
d as the beta-secretase that cleaves the amyloid precursor protein (APP) to
produce the N terminus of the A beta peptide found in plaques in the brain
s of Alzheimer's disease patients. BACE is an aspartic protease similar to
pepsin and renin. Comparative modeling of the three-dimensional structure o
f BACE in complex with its substrate shows that several residues confer spe
cificity of the enzyme for APP. In particular, Arg296 forms a salt-bridge w
ith the P1' Asp of the APP substrate, explaining the unusual preference of
BACE among aspartic proteases for a P1' residue that is negatively charged.
Several hydrophobic residues in the enzyme form a pocket for the P1 hydrop
hobic residue (Met in wild-type APP and Leu in APP with the "Swedish mutati
on" associated with early-onset of Alzheimer's disease). Inhibitors that ca
n bind to the BACE active site may prove useful for drugs to treat and prev
ent Alzheimer's disease. (C) 2000 Academic Press.