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From Proteopedia
Crystal Structure of Human Beta Secretase Complexed with Spiropiperdine Iminohydantoin Inhibitor
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 PubMedA high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed. Discovery and X-ray crystallographic analysis of a spiropiperidine iminohydantoin inhibitor of beta-secretase.,Barrow JC, Stauffer SR, Rittle KE, Ngo PL, Yang Z, Selnick HG, Graham SL, Munshi S, McGaughey GB, Holloway MK, Simon AJ, Price EA, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Espeseth AS, Xu M, Huang Q, Wolfe A, Pietrak B, Zuck P, Levorse DA, Hazuda D, Vacca JP J Med Chem. 2008 Oct 23;51(20):6259-62. Epub 2008 Sep 24. PMID:18811140[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Memapsin 2 | Munshi, S | Aspartyl protease | Bace | Glycoprotein | Hydrolase | Membrane | Protease | Transmembrane | Zymogen
