2WNC

Crystal structure of Aplysia ACHBP in complex with tropisetron


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal alpha7 nicotinic acetylcholine receptor.

Hibbs, R.E.Sulzenbacher, G.Shi, J.Talley, T.T.Conrod, S.Kem, W.R.Taylor, P.Marchot, P.Bourne, Y.

(2009) EMBO J 28: 3040-3051

  • DOI: https://doi.org/10.1038/emboj.2009.227
  • Primary Citation of Related Structures:  
    2WN9, 2WNC, 2WNJ, 2WNL

  • PubMed Abstract: 

    The pentameric acetylcholine-binding protein (AChBP) is a soluble surrogate of the ligand binding domain of nicotinic acetylcholine receptors. Agonists bind within a nest of aromatic side chains contributed by loops C and F on opposing faces of each subunit interface. Crystal structures of Aplysia AChBP bound with the agonist anabaseine, two partial agonists selectively activating the alpha7 receptor, 3-(2,4-dimethoxybenzylidene)-anabaseine and its 4-hydroxy metabolite, and an indole-containing partial agonist, tropisetron, were solved at 2.7-1.75 A resolution. All structures identify the Trp 147 carbonyl oxygen as the hydrogen bond acceptor for the agonist-protonated nitrogen. In the partial agonist complexes, the benzylidene and indole substituent positions, dictated by tight interactions with loop F, preclude loop C from adopting the closed conformation seen for full agonists. Fluctuation in loop C position and duality in ligand binding orientations suggest molecular bases for partial agonism at full-length receptors. This study, while pointing to loop F as a major determinant of receptor subtype selectivity, also identifies a new template region for designing alpha7-selective partial agonists to treat cognitive deficits in mental and neurodegenerative disorders.


  • Organizational Affiliation

    Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Soluble acetylcholine receptor
A, B, C, D, E
227Aplysia californicaMutation(s): 0 
UniProt
Find proteins for Q8WSF8 (Aplysia californica)
Explore Q8WSF8 
Go to UniProtKB:  Q8WSF8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8WSF8
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
TKT Binding MOAD:  2WNC Kd: 479 (nM) from 1 assay(s)
PDBBind:  2WNC Kd: 479 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.212 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.178 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 212.584α = 90
b = 212.584β = 90
c = 212.584γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-09-01
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Refinement description, Version format compliance
  • Version 1.2: 2018-06-13
    Changes: Data collection, Database references, Source and taxonomy, Structure summary
  • Version 1.3: 2019-04-03
    Changes: Data collection, Source and taxonomy
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description