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

Z Yang; B A Cromer; Robert J Harvey; M W Parker; J W Lynch

doi:10.1111/j.1471-4159.2007.04850.x

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

Journal article

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

Z Yang, B A Cromer, Robert J Harvey, M W Parker and J W Lynch

Journal of Neurochemistry, Vol.103(2), pp.580-589

2007

DOI: https://doi.org/10.1111/j.1471-4159.2007.04850.x

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Abstract

binding site

chloride channel

cys-loop receptor

ligand-gated ion channel

molecular structure and function

site-directed mutagenesis

Picrotoxin, an antagonist of structurally-rated GABAA receptors (GABAARs) 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 dimethylmethanol in place of the PTXININ isopropenyl group. Although the homomeric α1 GlyR is equally sensitive to both compounds, we show here that homomeric α2 and α3 GlyRs, like most GABAARs, are selectively inhibited by PTXININ. As conservative mutations to pore-lining 6â€² threonines equally affect the sensitivity of the α1 GlyR to both compounds, we conclude that PTXININ and PTN bind to 6â€² threonines by hydrogen bonding with exocyclic oxygens common to both molecules. In contrast, substitution of the 2â€² pore-lining glycine by serine selectively reduces PTN sensitivity, whereas the introduction of 2â€² alanines selectively increases PTXININ sensitivity. These results define the orientation of PTXININ and PTN binding in the α1 GlyR pore and allow us to conclude that the relatively reduced sensitivity of PTN at GABAARs and α2 and α3 GlyRs is due predominantly to its larger size and reduced ability to form hydrophobic interactions with 2â€² alanines. © 2007 The Authors.

Details

Title: A proposed structural basis for picrotoxinin and picrotin binding in the glycine receptor pore
Authors: Z Yang (Author) - University of Queensland
B A Cromer (Author) - St. Vincent's Institute of Medical Research
Robert J Harvey (Author) - University College London, United Kingdom
M W Parker (Author) - St. Vincent's Institute of Medical Research
J W Lynch (Author) - University of Queensland
Publication details: Journal of Neurochemistry, Vol.103(2), pp.580-589
Publisher: Wiley-Blackwell Publishing Ltd.
DOI: 10.1111/j.1471-4159.2007.04850.x
ISSN: 0022-3042
Organisation Unit: Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy; School of Health and Sport Sciences - Legacy; University of the Sunshine Coast, Queensland; School of Health
Language: English
Record Identifier: 99450925102621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Neurosciences

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