PUBLICATION
Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase
- Authors
- Sauder, J.M., Arthur, J.W., and Dunbrack, R.L. Jr.
- ID
- ZDB-PUB-100302-25
- Date
- 2000
- Source
- Journal of molecular biology 300(2): 241-248 (Journal)
- Registered Authors
- Keywords
- BACE, APP, Alzheimer’s disease, aspartic protease, homology modeling
- MeSH Terms
-
- Alzheimer Disease/enzymology*
- Alzheimer Disease/genetics
- Amino Acid Sequence
- Amyloid Precursor Protein Secretases
- Amyloid beta-Protein Precursor/chemistry
- Amyloid beta-Protein Precursor/metabolism*
- Animals
- Arginine/metabolism
- Aspartic Acid/metabolism
- Aspartic Acid Endopeptidases/chemistry*
- Aspartic Acid Endopeptidases/genetics
- Aspartic Acid Endopeptidases/metabolism*
- Binding Sites
- Crystallography, X-Ray
- Endopeptidases
- Humans
- Hydrogen Bonding
- Models, Molecular*
- Molecular Sequence Data
- Mutation
- Protein Conformation
- Sequence Alignment
- Static Electricity
- Substrate Specificity
- PubMed
- 10873463 Full text @ J. Mol. Biol.
Citation
Sauder, J.M., Arthur, J.W., and Dunbrack, R.L. Jr. (2000) Modeling of substrate specificity of the Alzheimer's disease amyloid precursor protein beta-secretase. Journal of molecular biology. 300(2):241-248.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping