Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedStarting from peptidomimetic BACE-1 inhibitors, the P2 amino acid including the P2/P3 peptide bond was replaced by a rigid 3-aminomethyl cyclohexane carboxylic acid. Co-crystallization revealed an unexpected binding mode with the P3/P4 amide bond placed into the S3 pocket resulting in a new hydrogen bond interaction pattern. Further optimization based on this structure resulted in highly potent BACE-1 inhibitors with selectivity over BACE-2 and cathepsin D. Structure-based design and synthesis of novel P2/P3 modified, non-peptidic beta-secretase (BACE-1) inhibitors.,Hanessian S, Shao Z, Betschart C, Rondeau JM, Neumann U, Tintelnot-Blomley M Bioorg Med Chem Lett. 2010 Mar 15;20(6):1924-7. Epub 2010 Feb 2. PMID:20172717[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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