5mco

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE INHIBITOR GRL-8234 AND EXOSITE PEPTIDE

spinqualitylabelsall models 5mco, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mco is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.49Å Ligands: ACE, BSD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidbeta (Abeta) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Abeta levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Abeta. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Abeta Levels Mediated by Brain Shuttle Transport.,Ruderisch N, Schlatter D, Kuglstatter A, Guba W, Huber S, Cusulin C, Benz J, Rufer AC, Hoernschemeyer J, Schweitzer C, Bulau T, Gartner A, Hoffmann E, Niewoehner J, Patsch C, Baumann K, Loetscher H, Kitas E, Freskgard PO EBioMedicine. 2017 Sep 7. pii: S2352-3964(17)30351-1. doi:, 10.1016/j.ebiom.2017.09.004. PMID:28923680 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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