1H23

Structure of acetylcholinesterase (E.C. 3.1.1.7) complexed with (S,S)-(-)-bis(12)-hupyridone at 2.15A resolution


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

Acetylcholinesterase Complexed with Bivalent Ligands Related to Huperzine A: Experimental Evidence for Species-Dependent Protein-Ligand Complementarity

Wong, D.M.Greenblatt, H.M.Dvir, H.Carlier, P.R.Han, Y.F.Pang, Y.P.Silman, I.Sussman, J.L.

(2003) J Am Chem Soc 125: 363

  • DOI: https://doi.org/10.1021/ja021111w
  • Primary Citation of Related Structures:  
    1H22, 1H23

  • PubMed Abstract: 

    Acetylcholinesterase (AChE) inhibitors improve the cognitive abilities of Alzheimer patients. (-)-Huperzine A [(-)-HupA], an alkaloid isolated from the club moss, Huperzia serrata, is one such inhibitor, but the search for more potent and selective drugs continues. Recently, alkylene-linked dimers of 5-amino-5,6,7,8-tetrahydroquinolinone (hupyridone, 1a), a fragment of HupA, were shown to serve as more potent inhibitors of AChE than (-)-HupA and monomeric 1a. We soaked two such dimers, (S,S)-(-)-bis(10)-hupyridone [(S,S)-(-)-2a] and (S,S)-(-)-bis(12)-hupyridone [(S,S)-(-)-2b] containing, respectively, 10 and 12 methylenes in the spacer, into trigonal TcAChE crystals, and solved the X-ray structures of the resulting complexes using the difference Fourier technique, both to 2.15 A resolution. The structures revealed one HupA-like 1a unit bound to the "anionic" subsite of the active-site, near the bottom of the active-site gorge, adjacent to Trp84, as seen for the TcAChE/(-)-HupA complex, and the second 1a unit near Trp279 in the "peripheral" anionic site at the top of the gorge, both bivalent molecules thus spanning the active-site gorge. The results confirm that the increased affinity of the dimeric HupA analogues for AChE is conferred by binding to the two "anionic" sites of the enzyme. Inhibition data show that (-)-2a binds to TcAChE approximately 6-7- and > 170-fold more tightly than (-)-2b and (-)-HupA, respectively. In contrast, previous data for rat AChE show that (-)-2b binds approximately 3- and approximately 2-fold more tightly than (-)-2a and (-)-HupA, respectively. Structural comparison of TcAChE with rat AChE, as represented by the closely related mouse AChE structure (1maa.pdb), reveals a narrower gorge for rat AChE, a perpendicular alignment of the Tyr337 ring to the gorge axis, and its conformational rigidity, as a result of hydrogen bonding between its hydroxyl group and that of Tyr341, relative to TcAChE Phe330. These structural differences in the active-site gorge explain the switch in inhibitory potency of (-)-2a and 2b and the larger dimer/(-)-HupA potency ratios observed for TcAChE relative to rat AChE. The results offer new insights into factors affecting protein-ligand complementarity within the gorge and should assist the further development of improved AChE inhibitors.


  • 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
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
E12
Query on E12

Download Ideal Coordinates CCD File 
B [auth A](S,S)-(-)-N,N'-DI-5'-[5',6',7',8'-TETRAHYDRO- 2'(1'H)-QUINOLYNYL]-1,12-DIAMINODODECANE DIHYDROCHLORIDE
C30 H46 N4 O2
VFFGYPZORQBRNM-UIOOFZCWSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
E12 PDBBind:  1H23 Ki: 4.5 (nM) from 1 assay(s)
BindingDB:  1H23 Ki: 4.5 (nM) from 1 assay(s)
IC50: 16 (nM) from 1 assay(s)
Binding MOAD:  1H23 Ki: 4.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.794α = 90
b = 111.794β = 90
c = 137.775γ = 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: 2002-12-23
    Type: Initial release
  • Version 1.1: 2011-08-31
    Changes: Advisory, Atomic model, Derived calculations, Non-polymer description, Other, Refinement description, Version format compliance
  • Version 1.2: 2014-01-22
    Changes: Database references
  • Version 1.3: 2019-04-03
    Changes: Data collection, Database references, Derived calculations, Experimental preparation, Other
  • Version 1.4: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Data collection, Derived calculations, Structure summary
  • Version 1.5: 2021-05-12
    Changes: Derived calculations, Structure summary
  • Version 1.6: 2023-12-13
    Changes: Data collection, Database references, Refinement description