2G94

Crystal structure of beta-secretase bound to a potent and highly selective inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.

Ghosh, A.K.Kumaragurubaran, N.Hong, L.Lei, H.Hussain, K.A.Liu, C.F.Devasamudram, T.Weerasena, V.Turner, R.Koelsch, G.Bilcer, G.Tang, J.

(2006) J Am Chem Soc 128: 5310-5311

  • DOI: https://doi.org/10.1021/ja058636j
  • Primary Citation of Related Structures:  
    2G94

  • PubMed Abstract: 

    Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.


  • Organizational Affiliation

    Department of Chemistry, Purdue University, West Lafayette, Indiana 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 
Gene Names: BACE1BACE
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
ZPQ
Query on ZPQ

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B],
G [auth C],
H [auth D]
N~2~-[(2R,4S,5S)-5-{[N-{[(3,5-DIMETHYL-1H-PYRAZOL-1-YL)METHOXY]CARBONYL}-3-(METHYLSULFONYL)-L-ALANYL]AMINO}-4-HYDROXY-2,7-DIMETHYLOCTANOYL]-N-ISOBUTYL-L-VALINAMIDE
C30 H54 N6 O8 S
OFAZWNGNAATRSH-GWCXRDAXSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
ZPQ PDBBind:  2G94 Ki: 0.3 (nM) from 1 assay(s)
Binding MOAD:  2G94 Ki: 0.3 (nM) from 1 assay(s)
BindingDB:  2G94 Ki: 0.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.199 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.628α = 90
b = 131.024β = 97.39
c = 88.236γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-04-25
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description