5l4h
From Proteopedia
X-ray structure of the 2-22' locally-closed mutant of GLIC in complex with 5-(2-BROMO-ETHYL)-5-ETHYL-PYRIMIDINE-2,4,6-TRIONE (brominated barbiturate)
Structural highlights
Function[GLIC_GLOVI] Cationic channel with similar permeabilities for Na(+) and K(+), that is activated by an increase of the proton concentration on the extracellular side. Displays no permeability for chloride ions. Shows slow kinetics of activation, no desensitization and a single channel conductance of 8 pS. Might contribute to adaptation to external pH change.[1] Publication Abstract from PubMedBarbiturates 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 helped to 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 barbiturates inhibition of cationic pLGICs and allows the rationalisation of several structural and functional features previously observed for barbiturates. Barbiturates bind in the GLIC ion channel pore and cause inhibition by stabilizing a closed state.,Fourati Z, Ruza RR, Laverty D, Drege E, Delarue-Cochin S, Joseph D, Koehl P, Smart T, Delarue M J Biol Chem. 2016 Dec 16. pii: jbc.M116.766964. PMID:27986812[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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