2VKM

Crystal structure of GRL-8234 bound to BACE (Beta-secretase)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.202 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Potent Memapsin 2 (Beta-Secretase) Inhibitors: Design, Synthesis, Protein-Ligand X-Ray Structure, and in Vivo Evaluation.

Ghosh, A.K.Kumaragurubaran, N.Hong, L.Kulkarni, S.Xu, X.Miller, H.B.Reddy, D.S.Weerasena, V.Turner, R.Chang, W.Koelsch, G.Tang, J.

(2008) Bioorg Med Chem Lett 18: 1031

  • DOI: https://doi.org/10.1016/j.bmcl.2007.12.028
  • Primary Citation of Related Structures:  
    2VKM

  • PubMed Abstract: 

    Structure-based design, synthesis, and biological evaluation of a series of peptidomimetic beta-secretase inhibitors incorporating hydroxyethylamine isosteres are described. We have identified inhibitor 24 which has shown exceedingly potent activity in memapsin 2 enzyme inhibitory (K(i) 1.8 nM) and cellular (IC(50)=1 nM in Chinese hamster ovary cells) assays. Inhibitor 24 has also shown very impressive in vivo properties (up to 65% reduction of plasma A beta) in transgenic mice. The X-ray structure of protein-ligand complex of memapsin 2 revealed critical interactions in the memapsin 2 active site.


  • Organizational Affiliation

    Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1
A, B, C, D
389Homo sapiensMutation(s): 0 
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
BSD
Query on BSD

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B],
G [auth C],
H [auth D]
N-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide
C36 H42 N4 O6 S
HIQWWDCRULXYDF-SWROZOJRSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BSD Binding MOAD:  2VKM Ki: 1.8 (nM) from 1 assay(s)
BindingDB:  2VKM Ki: 1.8 (nM) from 1 assay(s)
IC50: min: 1, max: 2.5 (nM) from 2 assay(s)
PDBBind:  2VKM Ki: 1.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.202 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.704α = 90
b = 130.308β = 97.41
c = 87.711γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-12-16
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description