3KN0

Structure of BACE bound to SCH708236

Summary for 3KN0

• Entry DOI: 10.2210/pdb3kn0/pdb
• Related: 3KMX 3KMY
• Descriptor: Beta-secretase 1, 3-[2-(3-{[(furan-2-ylmethyl)(methyl)amino]methyl}phenyl)ethyl]pyridin-2-amine, L(+)-TARTARIC ACID, ... (4 entities in total)
• Functional Keywords: bace1, alzheimer's, alternative splicing, aspartyl protease, disulfide bond, endoplasmic reticulum, endosome, glycoprotein, golgi apparatus, hydrolase, membrane, polymorphism, protease, transmembrane, zymogen
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 2
• Total formula weight: 88990.26

Authors

Strickland, C.,Wang, Y. (deposition date: 2009-11-11, release date: 2010-01-19, Last modification date: 2024-10-16)

Primary citation

Wang, Y.S.,Strickland, C.,Voigt, J.H.,Kennedy, M.E.,Beyer, B.M.,Senior, M.M.,Smith, E.M.,Nechuta, T.L.,Madison, V.S.,Czarniecki, M.,McKittrick, B.A.,Stamford, A.W.,Parker, E.M.,Hunter, J.C.,Greenlee, W.J.,Wyss, D.F.
Application of Fragment-Based NMR Screening, X-ray Crystallography, Structure-Based Design, and Focused Chemical Library Design to Identify Novel muM Leads for the Development of nM BACE-1 (beta-Site APP Cleaving Enzyme 1) Inhibitors.
J.Med.Chem., 53:942-950, 2010

PubMed Abstract: Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper

PubMed: 20043700
DOI: 10.1021/jm901472u

Experimental method

X-RAY DIFFRACTION (1.9 Å)