4LXM

Crystal Structure of Human Beta Secretase in Complex with compound 12a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides.

Rueeger, H.Lueoend, R.Machauer, R.Veenstra, S.J.Jacobson, L.H.Staufenbiel, M.Desrayaud, S.Rondeau, J.M.Mobitz, H.Neumann, U.

(2013) Bioorg Med Chem Lett 23: 5300-5306

  • DOI: https://doi.org/10.1016/j.bmcl.2013.07.071
  • Primary Citation of Related Structures:  
    4LXA, 4LXK, 4LXM

  • PubMed Abstract: 

    Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Aβ following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.


  • Organizational Affiliation

    Department of Global Discovery Chemistry, Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. heinrich.rueeger@novartis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B, C
402Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1KIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1YU
Query on 1YU

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
(1S,3S,4S,5R)-3-{4-amino-3-fluoro-5-[(1,1,1,3,3,3-hexafluoropropan-2-yl)oxy]benzyl}-5-[(3-tert-butylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1-oxide
C26 H31 F7 N2 O3 S
SVZBUJIOBQPGEC-DAMLKHMOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1YU PDBBind:  4LXM IC50: 88 (nM) from 1 assay(s)
Binding MOAD:  4LXM IC50: 88 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.29α = 90
b = 104.447β = 104.3
c = 100.487γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
CNXphasing
CNXrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-28
    Type: Initial release
  • Version 1.1: 2013-10-23
    Changes: Other
  • Version 1.2: 2013-11-20
    Changes: Database references
  • Version 1.3: 2017-11-15
    Changes: Refinement description