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| http://purl.uniprot.org/citations/11922623 | http://www.w3.org/2000/01/rdf-schema#comment | "beta-Secretase, also known as BACE, is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide. The activity of beta-secretase is the rate-limiting step of brain plaques production in vivo, and hence is a potential target for disease modifying drugs for Alzheimer's disease. To better understand the mechanism of action of beta-secretase and help explore novel strategies for drug discovery for Alzheimer's disease, it is important to elucidate the three-dimensional structure of its zymogen. Based on the X-ray structure of the enzyme's protease domain and the X-ray structure of pepsinogen, a model of the three-dimensional structure of the beta-secretase zymogen has been constructed. Comparison of the computed structure of pro-BACE with X-ray structures of pepsinogen and progastricsin (two other pro-aspartyl proteases) reveals a significant difference in the relationship of the pro-segment to the catalytic aspartates. In both pepsinogen and progastricsin a lysine side-chain in the pro-segment forms a salt bridge to the two catalytic aspartates, occupying the position normally occupied by a catalytic water. In the pro-BACE model there is no salt bridge, and the corresponding residue-a proline-does not interact at all with the catalytic residues. These findings can be used to elucidate the recent observations that the pro-domain of beta-secretase does not suppress activity as in a strict zymogen but does appear to facilitate proper folding of an active protease domain. The predicted three-dimensional structure of beta-secretase zymogen and the relevant findings might also provide useful insights for rational design of effective drugs against Alzheimer's disease."xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.org/dc/terms/identifier | "doi:10.1006/bbrc.2002.6686"xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/author | "Howe W.J."xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/author | "Chou K.C."xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/date | "2002"xsd:gYear |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/name | "Biochem Biophys Res Commun"xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/pages | "702-708"xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/title | "Prediction of the tertiary structure of the beta-secretase zymogen."xsd:string |
| http://purl.uniprot.org/citations/11922623 | http://purl.uniprot.org/core/volume | "292"xsd:string |
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