1UT6

Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with N-9-(1',2',3',4'-Tetrahydroacridinyl)-1,8- diaminooctane at 2.4 angstroms resolution.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Complexes of Alkylene-Linked Tacrine Dimers with Torpedo Californica Acetylcholinesterase: Binding of Bis(5)-Tacrine Produces a Dramatic Rearrangement in the Active-Site Gorge.

Rydberg, E.H.Brumshtein, B.Greenblatt, H.M.Wong, D.M.Shaya, D.Williams, L.D.Carlier, P.R.Pang, Y.-P.Silman, I.Sussman, J.L.

(2006) J Med Chem 49: 5491

  • DOI: https://doi.org/10.1021/jm060164b
  • Primary Citation of Related Structures:  
    1ODC, 1UT6, 2CKM, 2CMF

  • PubMed Abstract: 

    The X-ray crystal structures were solved for complexes with Torpedo californica acetylcholinesterase of two bivalent tacrine derivative compounds in which the two tacrine rings were separated by 5- and 7-carbon spacers. The derivative with the 7-carbon spacer spans the length of the active-site gorge, making sandwich interactions with aromatic residues both in the catalytic anionic site (Trp84 and Phe330) at the bottom of the gorge and at the peripheral anionic site near its mouth (Tyr70 and Trp279). The derivative with the 5-carbon spacer interacts in a similar manner at the bottom of the gorge, but the shorter tether precludes a sandwich interaction at the peripheral anionic site. Although the upper tacrine group does interact with Trp279, it displaces the phenyl residue of Phe331, thus causing a major rearrangement in the Trp279-Ser291 loop. The ability of this inhibitor to induce large-scale structural changes in the active-site gorge of acetylcholinesterase has significant implications for structure-based drug design because such conformational changes in the target enzyme are difficult to predict and to model.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINESTERASE537Tetronarce 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
A8N
Query on A8N

Download Ideal Coordinates CCD File 
D [auth A]N-9-(1',2',3',4'-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE
C21 H33 N3
LFBAUYQQFKFFCF-UHFFFAOYSA-P
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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.194 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.193α = 90
b = 111.193β = 90
c = 136.853γ = 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: 2005-04-21
    Type: Initial release
  • Version 1.1: 2016-09-28
    Changes: Database references, Derived calculations, Non-polymer description, Other, Source and taxonomy, Structure summary, Version format compliance
  • Version 1.2: 2019-04-03
    Changes: Data collection, Database references, Derived calculations, Experimental preparation, Other
  • Version 1.3: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Other, Structure summary
  • Version 1.4: 2021-05-12
    Changes: Derived calculations, Structure summary
  • Version 1.5: 2023-12-13
    Changes: Data collection, Database references, Refinement description