J Michael Sauder - Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase

Version 1

      Publication Details (including relevant citation   information):

      J Mol Biol (2000) 300: 241-248.

      Sauder JM, Arthur JW, Dunbrack RL Jr


      The enzyme BACE (beta-site APP-cleaving enzyme) has recently   been  identified as the beta-secretase that cleaves the   amyloid precursor  protein (APP) to produce the N terminus   of the Abeta peptide found in  plaques in the brains of   Alzheimer's disease patients. BACE is an  aspartic protease   similar to pepsin and renin. Comparative modeling of  the   three-dimensional structure of BACE in complex with its   substrate  shows that several residues confer specificity of   the enzyme for APP. In  particular, Arg296 forms a   salt-bridge with 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 hydrophobic  residue (Met in wild-type APP and   Leu in APP with the "Swedish mutation"  associated with   early-onset of Alzheimer's disease). Inhibitors that  can   bind to the BACE active site may prove useful for drugs to treat   and  prevent Alzheimer's disease.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/10873463