3ZMG

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH CHEMICAL LIGAND


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.74 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Beta-Secretase (Bace1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer'S Disease.

Hilpert, H.Guba, W.Woltering, T.J.Wostl, W.Pinard, E.Mauser, H.Mayweg, A.V.Rogers-Evans, M.Humm, R.Krummenacher, D.Muser, T.Schnider, C.Jacobsen, H.Ozmen, L.Bergadano, A.Banner, D.W.Hochstrasser, R.Kuglstatter, A.David-Pierson, P.Fischer, H.Polara, A.Narquizian, R.

(2013) J Med Chem 56: 3980

  • DOI: https://doi.org/10.1021/jm400225m
  • Primary Citation of Related Structures:  
    3ZLQ, 3ZMG, 4J0P, 4J0T, 4J0V, 4J0Y, 4J0Z, 4J17, 4J1C, 4J1E, 4J1F, 4J1H, 4J1I, 4J1K

  • PubMed Abstract: 

    An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.


  • Organizational Affiliation

    Discovery Chemistry, Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland. hans.hilpert@roche.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1409Homo sapiensMutation(s): 1 
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6Z0
Query on 6Z0

Download Ideal Coordinates CCD File 
B [auth A]N-[3-[(4R)-2-azanylidene-5,5-bis(fluoranyl)-4-methyl-1,3-oxazinan-4-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide
C18 H14 F3 N5 O2
DVMUZHLUMHPCGZ-QGZVFWFLSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
E [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6Z0 PDBBind:  3ZMG IC50: 23 (nM) from 1 assay(s)
Binding MOAD:  3ZMG IC50: 23 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.74 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.177 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.519α = 90
b = 102.519β = 90
c = 171.805γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SADABSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2013-06-05
    Changes: Database references
  • Version 1.2: 2019-01-30
    Changes: Data collection, Derived calculations, Experimental preparation
  • Version 1.3: 2019-02-06
    Changes: Data collection, Experimental preparation