5L4E

X-ray structure of the 2-22' locally-closed mutant of GLIC in complex with thiopental


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State.

Fourati, Z.Ruza, R.R.Laverty, D.Drege, E.Delarue-Cochin, S.Joseph, D.Koehl, P.Smart, T.Delarue, M.

(2017) J Biol Chem 292: 1550-1558

  • DOI: https://doi.org/10.1074/jbc.M116.766964
  • Primary Citation of Related Structures:  
    5L47, 5L4E, 5L4H

  • PubMed Abstract: 

    Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound to GLIC, a cationic prokaryotic pLGIC with excellent structural homology to other relevant channels sensitive to general anesthetics and, as shown here, to barbiturates, at clinically relevant concentrations. Several derivatives of barbiturates containing anomalous scatterers were synthesized, and these derivatives helped us unambiguously identify a unique barbiturate binding site within the central ion channel pore in a closed conformation. In addition, docking calculations around the observed binding site for all three states of the receptor, including a model of the desensitized state, showed that barbiturates preferentially stabilize the closed state. The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates.


  • Organizational Affiliation

    From the Unité de Dynamique Structurale des Macromolécules, UMR 3528 du CNRS, Institut Pasteur, 75015 Paris, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proton-gated ion channel
A, B, C, D, E
317GloeobacterMutation(s): 0 
Gene Names: glvIglr4197
Membrane Entity: Yes 
UniProt
Find proteins for Q7NDN8 (Gloeobacter violaceus (strain ATCC 29082 / PCC 7421))
Explore Q7NDN8 
Go to UniProtKB:  Q7NDN8
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ7NDN8
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.50 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 182.025α = 90
b = 134.581β = 101.88
c = 159.018γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French National Research AgencyFrance13BSV8002002

Revision History  (Full details and data files)

  • Version 1.0: 2016-12-21
    Type: Initial release
  • Version 1.1: 2016-12-28
    Changes: Database references
  • Version 1.2: 2017-02-15
    Changes: Database references
  • Version 1.3: 2017-09-06
    Changes: Advisory, Author supporting evidence