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

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 6′ threonines equally affect the sensitivity of the α1 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 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 2′ alanines.