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 

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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]
B [auth A],
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [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)
Binding MOAD:  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 


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