1E66

STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH (-)-HUPRINE X AT 2.1A RESOLUTION


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


This is version 2.3 of the entry. See complete history


Literature

3D Structure of Torpedo Californica Acetylcholinesterase Complexed with Huprine X at 2. 1 A Resolution: Kinetic and Molecular Dynamic Correlates.

Dvir, H.Wong, D.M.Harel, M.Barril, X.Orozco, M.Luque, F.J.Munoz-Torrero, D.Camps, P.Rosenberry, T.L.Silman, I.Sussman, J.L.

(2002) Biochemistry 41: 2970

  • DOI: https://doi.org/10.1021/bi011652i
  • Primary Citation of Related Structures:  
    1E66

  • PubMed Abstract: 

    Huprine X is a novel acetylcholinesterase (AChE) inhibitor, with one of the highest affinities reported for a reversible inhibitor. It is a synthetic hybrid that contains the 4-aminoquinoline substructure of one anti-Alzheimer drug, tacrine, and a carbobicyclic moiety resembling that of another AChE inhibitor, (-)-huperzine A. Cocrystallization of huprine X with Torpedo californica AChE yielded crystals whose 3D structure was determined to 2.1 A resolution. The inhibitor binds to the anionic site and also hinders access to the esteratic site. Its aromatic portion occupies the same binding site as tacrine, stacking between the aromatic rings of Trp84 and Phe330, whereas the carbobicyclic unit occupies the same binding pocket as (-)-huperzine A. Its chlorine substituent was found to lie in a hydrophobic pocket interacting with rings of the aromatic residues Trp432 and Phe330 and with the methyl groups of Met436 and Ile439. Steady-state inhibition data show that huprine X binds to human AChE and Torpedo AChE 28- and 54-fold, respectively, more tightly than tacrine. This difference stems from the fact that the aminoquinoline moiety of huprine X makes interactions similar to those made by tacrine, but additional bonds to the enzyme are made by the huperzine-like substructure and the chlorine atom. Furthermore, both tacrine and huprine X bind more tightly to Torpedo than to human AChE, suggesting that their quinoline substructures interact better with Phe330 than with Tyr337, the corresponding residue in the human AChE structure. Both (-)-huperzine A and huprine X display slow binding properties, but only binding of the former causes a peptide flip of Gly117.


  • Organizational Affiliation

    Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel, 76100.


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
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HUX
Query on HUX

Download Ideal Coordinates CCD File 
D [auth A]3-CHLORO-9-ETHYL-6,7,8,9,10,11-HEXAHYDRO-7,11-METHANOCYCLOOCTA[B]QUINOLIN-12-AMINE
C18 H19 Cl N2
QTPHSDHUHXUYFE-NWDGAFQWSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HUX Binding MOAD:  1E66 Ki: 0.13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.177 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 112.335α = 90
b = 112.335β = 90
c = 138.165γ = 120
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
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: 2001-08-02
    Type: Initial release
  • Version 1.1: 2011-08-31
    Changes: Derived calculations, Non-polymer description, Other, Refinement description, Structure summary, Version format compliance
  • Version 2.0: 2017-07-12
    Changes: Advisory, Atomic model, Derived calculations
  • Version 2.1: 2019-04-03
    Changes: Data collection, Experimental preparation
  • Version 2.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Other, Structure summary
  • Version 2.3: 2023-12-13
    Changes: Data collection, Database references, Refinement description, Structure summary