5T90

Structural mechanisms for alpha-conotoxin selectivity at the human alpha3beta4 nicotinic acetylcholine receptor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.219 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural mechanisms for alpha-conotoxin activity at the human alpha 3 beta 4 nicotinic acetylcholine receptor.

Abraham, N.Healy, M.Ragnarsson, L.Brust, A.Alewood, P.F.Lewis, R.J.

(2017) Sci Rep 7: 45466-45466

  • DOI: https://doi.org/10.1038/srep45466
  • Primary Citation of Related Structures:  
    5T90

  • PubMed Abstract: 

    Nicotinic acetylcholine receptors (nAChR) are therapeutic targets for a range of human diseases. α-Conotoxins are naturally occurring peptide antagonists of nAChRs that have been used as pharmacological probes and investigated as drug leads for nAChR related disorders. However, α-conotoxin interactions have been mostly characterised at the α7 and α3β2 nAChRs, with interactions at other subtypes poorly understood. This study provides novel structural insights into the molecular basis for α-conotoxin activity at α3β4 nAChR, a therapeutic target where subtype specific antagonists have potential to treat nicotine addiction and lung cancer. A co-crystal structure of α-conotoxin LsIA with Lymnaea stagnalis acetylcholine binding protein guided the design and functional characterisations of LsIA analogues that identified the minimum pharmacophore regulating α3β4 antagonism. Interactions of the LsIA R10F with β4 K57 and the conserved -NN- α-conotoxin motif with β4 I77 and I109 conferred α3β4 activity to the otherwise inactive LsIA. Using these structural insights, we designed LsIA analogues with α3β4 activity. This new understanding of the structural basis of protein-protein interactions between α-conotoxins and α3β4 may help rationally guide the development of α3β4 selective antagonists with therapeutic potential.


  • Organizational Affiliation

    IMB Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholine-binding protein
A, B, C, D, E
210Lymnaea stagnalisMutation(s): 0 
UniProt
Find proteins for P58154 (Lymnaea stagnalis)
Explore P58154 
Go to UniProtKB:  P58154
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP58154
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
LsIA
F, G, H, I, J
18ConusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.219 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 115.94α = 90
b = 124.5β = 90
c = 154.21γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Health and Medical Research Council (NHMRC, Australia)AustraliaAPP1072113

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-12
    Type: Initial release
  • Version 1.1: 2017-09-20
    Changes: Author supporting evidence, Data collection
  • Version 1.2: 2020-01-08
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description