A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore

Yang, Zhe, Cromer, Brett A., Harvey, Robert J., Parker, Michael W. and Lynch, Joseph W. (2007) A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore. Journal of Neurochemistry, 103 2: 580-589. doi:10.1111/j.1471-4159.2007.04850.x

Author Yang, Zhe
Cromer, Brett A.
Harvey, Robert J.
Parker, Michael W.
Lynch, Joseph W.
Title A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 0022-3042
Publication date 2007
Sub-type Article (original research)
DOI 10.1111/j.1471-4159.2007.04850.x
Volume 103
Issue 2
Start page 580
End page 589
Total pages 10
Editor A. J. Turner
B. Collie
Place of publication Oxford
Publisher Blackwell Publishing
Collection year 2008
Language eng
Subject C1
320702 Central Nervous System
780105 Biological sciences
06 Biological Sciences
Abstract Picrotoxin, an antagonist of structurally-rated GABAA receptors (GABA(A)Rs) and glycine receptors (GlyRs), is an equimolar mixture of picrotoxinin (PTXININ) and picrotin (PTN). These compounds share a common structure except that PTN contains a slightly larger climethylmethanol in place of the PTXININ isopropenyl group. Although the homomeric alpha 1 GlyR is equally sensitive to both compounds, we show here that homomeric alpha 2 and alpha 3 GlyRs, like most GABA(A)Rs, are selectively inhibited by PTXININ. As conservative mutations to pore-lining 6' threonines equally affect the sensitivity of the alpha 1 GlyR to both compounds, we conclude that PTXININ and PTN bind to 6' threonines by hydrogen bonding with exocyclic oxygens common to both molecules. In contrast, substitution of the 2' pore-lining glycine by serine selectively reduces PTN sensitivity, whereas the introduction of 2' alanines selectively increases PTXININ sensitivity. These results define the orientation of PTXININ and PTN binding in the all GlyR pore and allow us to conclude that the relatively reduced sensitivity of PTN at GABA(A)Rs and alpha 2 and alpha 3 GlyRs is due predominantly to its larger size and reduced ability to form hydrophobic interactions with 2' alanines.
Keyword Biochemistry & Molecular Biology
binding site
chloride channel
cys-loop receptor
ligand-gated ion channel
molecular structure and function
site-directed mutagenesis
Drosophila Gaba Receptor
Chloride Channels
Point Mutation
Q-Index Code C1
Q-Index Status Confirmed Code

Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 36 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 38 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 18 Feb 2008, 15:27:49 EST