4IVT

Crystal structure of BACE1 with its inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Virtual screening and structure-based discovery of indole acylguanidines as potent beta-secretase (BACE1) inhibitors

Zou, Y.Li, L.Chen, W.Y.Chen, T.T.Ma, L.Wang, X.Xiong, B.Xu, Y.C.Shen, J.

(2013) Molecules 18: 5706-5722

  • DOI: https://doi.org/10.3390/molecules18055706
  • Primary Citation of Related Structures:  
    4IVS, 4IVT

  • PubMed Abstract: 

    Proteolytic cleavage of amyloid precursor protein by β-secretase (BACE1) is a key step in generating the N-terminal of β-amyloid (Aβ), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Aβ and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co-crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design.


  • Organizational Affiliation

    State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1433Homo sapiensMutation(s): 2 
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VTI
Query on VTI

Download Ideal Coordinates CCD File 
B [auth A]N-{N-[4-(acetylamino)-3,5-dichlorobenzyl]carbamimidoyl}-2-(1H-indol-1-yl)acetamide
C20 H19 Cl2 N5 O2
PTYGSLKLIDGJBA-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
VTI PDBBind:  4IVT IC50: 1010 (nM) from 1 assay(s)
Binding MOAD:  4IVT IC50: 1010 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.191 
  • R-Value Work: 0.169 
  • R-Value Observed: 0.170 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 104.69α = 90
b = 128.84β = 90
c = 76.76γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
Blu-Icedata collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-13
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description