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

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Yang Z, Cromer BA, Harvey RJ, Parker MW, Lynch JW

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

J Neurochem. 2007 Oct;103(2):580-9. Epub 2007 Aug 20.

PubMed ID

17714449 [ View in PubMed

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Abstract

Picrotoxin, an antagonist of structurally-rated GABA(A) 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 dimethylmethanol in place of the PTXININ isopropenyl group. Although the homomeric alpha1 GlyR is equally sensitive to both compounds, we show here that homomeric alpha2 and alpha3 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 alpha1 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 alpha1 GlyR pore and allow us to conclude that the relatively reduced sensitivity of PTN at GABA(A)Rs and alpha2 and alpha3 GlyRs is due predominantly to its larger size and reduced ability to form hydrophobic interactions with 2' alanines.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Picrotoxin	Glycine receptor subunit alpha-2	Protein	Humans	Unknown	Antagonist	Details
Picrotoxin	Glycine receptor subunit alpha-3	Protein	Humans	Unknown	Antagonist	Details