3VV7

Crystal Structure of beta secetase in complex with 2-amino-6-((1S,2R)-2-(3'-methoxybiphenyl-3-yl)cyclopropyl)-3-methylpyrimidin-4(3H)-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.244 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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Literature

Conformational restriction approach to beta-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode.

Yonezawa, S.Yamamoto, T.Yamakawa, H.Muto, C.Hosono, M.Hattori, K.Higashino, K.Yutsudo, T.Iwamoto, H.Kondo, Y.Sakagami, M.Togame, H.Tanaka, Y.Nakano, T.Takemoto, H.Arisawa, M.Shuto, S.

(2012) J Med Chem 55: 8838-8858

  • DOI: https://doi.org/10.1021/jm3011405
  • Primary Citation of Related Structures:  
    3VV6, 3VV7, 3VV8

  • PubMed Abstract: 

    Improvement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.


  • Organizational Affiliation

    Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Kita-21 Nishi-11 Kita-ku, Sapporo 001-0021, Japan. shu@pharm.hokudai.ac.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1416Homo sapiensMutation(s): 0 
Gene Names: BACE1
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
0B1
Query on 0B1

Download Ideal Coordinates CCD File 
J [auth A]2-amino-6-[(1S,2R)-2-(3'-methoxybiphenyl-3-yl)cyclopropyl]-3-methylpyrimidin-4(3H)-one
C21 H21 N3 O2
QECXNBWGUGUPSI-ROUUACIJSA-N
IOD
Query on IOD

Download Ideal Coordinates CCD File 
B [auth A]
C [auth A]
D [auth A]
E [auth A]
F [auth A]
IODIDE ION
I
XMBWDFGMSWQBCA-UHFFFAOYSA-M
GOL
Query on GOL

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0B1 BindingDB:  3VV7 IC50: 4600 (nM) from 1 assay(s)
PDBBind:  3VV7 IC50: 4600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.280 
  • R-Value Work: 0.242 
  • R-Value Observed: 0.244 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.681α = 90
b = 103.681β = 90
c = 169.006γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 0B1Click on this verticalbar to view details

Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-24
    Type: Initial release
  • Version 1.1: 2013-09-04
    Changes: Database references
  • Version 1.2: 2024-11-20
    Changes: Data collection, Database references, Derived calculations, Structure summary