1W76

Orthorhombic form of Torpedo californica acetylcholinesterase (AChE) complexed with bis-acting galanthamine derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.236 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design.

Greenblatt, H.M.Guillou, C.Guenard, D.Argaman, A.Botti, S.Badet, B.Thal, C.Silman, I.Sussman, J.L.

(2004) J Am Chem Soc 126: 15405-15411

  • DOI: https://doi.org/10.1021/ja0466154
  • Primary Citation of Related Structures:  
    1W4L, 1W6R, 1W75, 1W76

  • PubMed Abstract: 

    Bifunctional derivatives of the alkaloid galanthamine, designed to interact with both the active site of the enzyme acetylcholinesterase (AChE) and its peripheral cation binding site, have been assayed with Torpedo californica AChE (TcAChE), and the three-dimensional structures of their complexes with the enzyme have been solved by X-ray crystallography. Differences were noted between the IC(50) values obtained for TcAChE and those for Electrophorus electricus AChE. These differences are ascribed to sequence differences in one or two residues lining the active-site gorge of the enzyme. The binding of one of the inhibitors disrupts the native conformation of one wall of the gorge, formed by the loop Trp279-Phe290. It is proposed that flexibility of this loop may permit the binding of inhibitors such as galanthamine, which are too bulky to penetrate the narrow neck of the gorge formed by Tyr121 and Phe330 as seen in the crystal structure.


  • Organizational Affiliation

    Departments of Structural Biology and Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE
A, B
543Tetronarce 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
Binding Affinity Annotations 
IDSourceBinding Affinity
GNT BindingDB:  1W76 Ki: 190 (nM) from 1 assay(s)
IC50: min: 360, max: 1069 (nM) from 6 assay(s)
PDBBind:  1W76 IC50: 702 (nM) from 1 assay(s)
Binding MOAD:  1W76 IC50: 702 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.236 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.223α = 90
b = 105.253β = 90
c = 150.559γ = 90
Software Package:
Software NamePurpose
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-11-25
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-04-03
    Changes: Data collection, Derived calculations, Experimental preparation, Other
  • Version 1.4: 2019-04-10
    Changes: Data collection, Database references
  • Version 1.5: 2019-05-22
    Changes: Data collection, Refinement description
  • Version 1.6: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Other, Structure summary