4zsp

BACE crystal structure with bicyclic aminothiazine inhibitor

spinqualitylabelsall models 4zsp, resolution 1.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zsp 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 1.91Å Ligands: 4RZ, GOL 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 The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1 research efforts, fragment screening revealed that bicyclic thiazine 3 had low millimolar activity against BACE1. Analysis of the co-crystal structure of 3 suggested that potency could be increased through extension toward the S3 pocket and through conformational constraint of the thiazine core. Pursuit of S3-binding groups produced low micromolar inhibitor 6, which informed the S3-design for constrained analogs 7 and 8, themselves prepared via independent, multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8 is described. Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.,Winneroski LL, Schiffler MA, Erickson JA, May PC, Monk SA, Timm DE, Audia JE, Beck JP, Boggs LN, Borders AR, Boyer RD, Brier RA, Hudziak KJ, Klimkowski VJ, Garcia Losada P, Mathes BM, Stout SL, Watson BM, Mergott DJ Bioorg Med Chem. 2015 Jul 1;23(13):3260-8. doi: 10.1016/j.bmc.2015.04.062. Epub, 2015 May 6. PMID:26001341 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA