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The answer lies in the fact that the molecule has two pos- itively charged nitrogen atoms (one tertiary, which is pro- tonated, and one quaternary).Such an interaction is extremely strong and would more than make up for the lack of the ester binding interaction.Originally, it was believed that the distance between the two centres (1.15 nm) might be equivalent to the distance between two separate cholin- ergic receptors and that the tubocurarine molecule could bridge the two binding sites, and act as a steric shield for both.It has now been proposed that one of the positively charged nitrogens on tubocurarine binds to the anionic binding region of an acetylcholine binding site, while the other binds to a nearby cysteine residue 0.9-1.2 nm away (Fig.Another possibility is that the tubocurarine molecule bridges two acetylcholine binding sites within the one protein complex.22.33 and section 22.11). 22.33).

The answer lies in the fact that the molecule has two pos- itively charged nitrogen atoms (one tertiary, which is pro- tonated, and one quaternary). Originally, it was believed that the distance between the two centres (1.15 nm) might be equivalent to the distance between two separate cholin- ergic receptors and that the tubocurarine molecule could bridge the two binding sites, and act as a steric shield for both. However pleasing that theory may be, the dimen- sions of the nicotinic receptor make this impossible. The nicotinic receptor is a protein dimer made up of two iden- tical protein complexes separated by 9–10 nm—far too large to be bridged by the tubocurarine molecule (Fig. 22.33 and section 22.11).
Another possibility is that the tubocurarine molecule bridges two acetylcholine binding sites within the one protein complex. As there are two such sites within the complex, this appears to be an attractive theory. However, the two sites are more than 1.15 nm apart and so this too has to be ruled out. It has now been proposed that one of the positively charged nitrogens on tubocurarine binds to the anionic binding region of an acetylcholine binding site, while the other binds to a nearby cysteine residue 0.9–1.2 nm away (Fig. 22.33).
Despite the uncertainty surrounding the binding interactions of tubocurarine, it seems highly probable that two ionic binding regions are involved. Such an interaction is extremely strong and would more than make up for the lack of the ester binding interaction. It is also clear that the distance between the two positively charged nitrogen atoms is crucial to activity. Therefore, analogues that retain this distance should also be good antagonists. Strong evidence for this comes from the fact that the simple molecule decamethonium is a good antagonist (section 22.10.2.2)