1HBJ

X-ray Crystal structure of complex between Torpedo californica AChE and a reversible inhibitor, 4-Amino-5-fluoro-2-methyl-3-(3-trifluoroacetylbenzylthiomethyl)quinoline


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

A Structure-Based Design Approach to the Development of Novel, Reversible Ache Inhibitors

Doucet-Personeni, C.Bentley, P.D.Fletcher, R.J.Kinkaid, A.Kryger, G.Pirard, B.Taylor, A.Taylor, R.Taylor, J.Viner, R.Silman, I.Sussman, J.L.Greenblatt, H.M.Lewis, T.L.

(2001) J Med Chem 44: 3203

  • DOI: https://doi.org/10.1021/jm010826r
  • Primary Citation of Related Structures:  
    1HBJ

  • PubMed Abstract: 

    Chimeras of tacrine and m-(N,N,N-Trimethylammonio)trifluoroacetophenone (1) were designed as novel, reversible inhibitors of acetylcholinesterase. On the basis of the X-ray structure of the apoenzyme, a molecular modeling study determined the favored attachment positions on the 4-aminoquinoline ring (position 3 and the 4-amino nitrogen) and the favored lengths of a polymethylene link between the two moieties (respectively 5-6 and 4-5 sp(3) atoms). Seven compounds matching these criteria were synthesized, and their inhibitory potencies were determined to be in the low nanomolar range. Activity data for close analogues lacking some of the postulated key features showed that our predictions were correct. In addition, a subsequent crystal structure of acetylcholinesterase complexed with the most active compound 27 was in good agreement with our model. The design strategy is therefore validated and can now be developed further.


  • Organizational Affiliation

    Syngenta, Jealott's Hill Research Station, Bracknell, Berkshire RG42 6EY, U.K.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE543Tetronarce californicaMutation(s): 0 
EC: 3.1.1.7
UniProt
Find proteins for P04058 (Tetronarce californica)
Explore P04058 
Go to UniProtKB:  P04058
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04058
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FBQ
Query on FBQ

Download Ideal Coordinates CCD File 
D [auth A]1-[3-({[(4-AMINO-5-FLUORO-2-METHYLQUINOLIN-3-YL)METHYL]THIO}METHYL)PHENYL]-2,2,2-TRIFLUOROETHANE-1,1-DIOL
C20 H18 F4 N2 O2 S
GPBGHVRNVGXPNM-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A]2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
MES
Query on MES

Download Ideal Coordinates CCD File 
E [auth A]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
PG4
Query on PG4

Download Ideal Coordinates CCD File 
F [auth A]TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FBQ PDBBind:  1HBJ IC50: 3 (nM) from 1 assay(s)
BindingDB:  1HBJ IC50: 1.10e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.183 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 112.332α = 90
b = 112.332β = 90
c = 137.073γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing
CNSphasing
CNSrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-09-25
    Type: Initial release
  • Version 1.1: 2013-06-19
    Changes: Derived calculations, Non-polymer description, Other, Refinement description, Structure summary, Version format compliance
  • Version 1.2: 2019-04-03
    Changes: Data collection, Derived calculations, Experimental preparation, Other
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 2.1: 2023-12-13
    Changes: Data collection, Database references, Refinement description, Structure summary