2P4J

Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.

Ghosh, A.K.Kumaragurubaran, N.Hong, L.Kulkarni, S.S.Xu, X.Chang, W.Weerasena, V.Turner, R.Koelsch, G.Bilcer, G.Tang, J.

(2007) J Med Chem 50: 2399-2407

  • DOI: https://doi.org/10.1021/jm061338s
  • Primary Citation of Related Structures:  
    2P4J

  • PubMed Abstract: 

    Structure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors.


  • 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
23I
Query on 23I

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B],
G [auth C],
H [auth D]
N-[(1S,2S,4R)-2-HYDROXY-1-ISOBUTYL-5-({(1S)-1-[(ISOPROPYLAMINO)CARBONYL]-2-METHYLPROPYL}AMINO)-4-METHYL-5-OXOPENTYL]-5-[METHYL(METHYLSULFONYL)AMINO]-N'-[(1R)-1-PHENYLETHYL]ISOPHTHALAMIDE
C36 H55 N5 O7 S
BJOCXJJVELLFKM-LLWRDSBASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
23I BindingDB:  2P4J Ki: 1.1 (nM) from 1 assay(s)
Binding MOAD:  2P4J Ki: 1.1 (nM) from 1 assay(s)
PDBBind:  2P4J Ki: 1.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.929α = 90
b = 129.969β = 97.48
c = 87.483γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
MAR345dtbdata collection
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-07-24
    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: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2023-08-30
    Changes: Data collection, Database references, Refinement description