3PI5

Crystal Structure of Human Beta Secretase in Complex with BFG356


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure based design, synthesis and SAR of cyclic hydroxyethylamine (HEA) BACE-1 inhibitors.

Rueeger, H.Rondeau, J.M.McCarthy, C.Mobitz, H.Tintelnot-Blomley, M.Neumann, U.Desrayaud, S.

(2011) Bioorg Med Chem Lett 21: 1942-1947

  • DOI: https://doi.org/10.1016/j.bmcl.2011.02.038
  • Primary Citation of Related Structures:  
    3PI5, 3QBH

  • PubMed Abstract: 

    This Letter describes the de novo design of non-peptidic hydroxyethylamine (HEA) inhibitors of BACE-1 by elimination of P-gp contributing amide attachments. The predicted binding mode of the novel cyclic sulfone HEA core template was confirmed in a X-ray co-crystal structure. Inhibitors of sub-micromolar potency with an improved property profile over historic HEA inhibitors resulting in improved brain penetration are described.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 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
3P5
Query on 3P5

Download Ideal Coordinates CCD File 
D [auth A],
E [auth B],
F [auth C]
(3S,4S,5R)-3-(3-bromo-4-hydroxybenzyl)-5-[(3-cyclopropylbenzyl)amino]tetrahydro-2H-thiopyran-4-ol 1,1-dioxide
C22 H26 Br N O4 S
NDEIDRFQAYLHLT-CBQOVEMMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3P5 PDBBind:  3PI5 IC50: 950 (nM) from 1 assay(s)
Binding MOAD:  3PI5 IC50: 950 (nM) from 1 assay(s)
BindingDB:  3PI5 IC50: 950 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.218 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.486α = 90
b = 102.416β = 104.45
c = 100.178γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
DENZOdata 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: 2011-03-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-03-01
    Changes: Other