4ke1

Crystal structure of BACE1 in complex with hydroxyethylamine-macrocyclic inhibitor 19

spinqualitylabelsall models 4ke1, resolution 1.91Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ke1 is a 1 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: 1R6, GOL, IOD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid beta-peptide (Abeta)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. Hydroxyethylamine-based inhibitors of BACE1: P1-P3 macrocyclization can improve potency, selectivity, and cell activity.,Pennington LD, Whittington DA, Bartberger MD, Jordan SR, Monenschein H, Nguyen TT, Yang BH, Xue QM, Vounatsos F, Wahl RC, Chen K, Wood S, Citron M, Patel VF, Hitchcock SA, Zhong W Bioorg Med Chem Lett. 2013 Aug 1;23(15):4459-64. doi: 10.1016/j.bmcl.2013.05.028., Epub 2013 May 16. PMID:23769639 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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