Within the ion channel pore there are 2 sites of constriction located at Pro266 and Leu277 which are present on the pore lining of the inner M2 helices of each sub-unit. More about respective pore sizes in the summary.
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| Figure 3. A view of the channel from the extracellular side of the GlyR showing the distances between Pro266 α-carbons on each chain in blue and Leu277 α-carbons in red. |
Strychnine binding:
The proximity of the carbonyl oxygen of strychnine and Thr220 of GlyR, along with hydrogen bonding between the same oxygen and Arg81 and the distortion of the strychnine aromatic rings by Phe79 and Tyr218 provoke binding between this antagonist and GlyR (figure 4).
Glycine binding:
Similar to strychnine, mutational analysis showed that glycine has two identical binding determinants to strychnine - Thr220 and Tyr218, with the majority of the affinity coming from the Thr220 interaction. Other residues involved include Arg81, Ser145, Phe175 and Phe223.
Ivermectin binding:
Ivermectin predominantly binds through interactions with hydrophobic residues present in the M3 and M1 helices. Hydrogen bonding also occurs with a variety of residues including Arg287 that allows for direct contact between ivermectin and the inner, pore-restricting M2 helices. Arg287 mutation causes significantly reduced ivermectin sensitivity - the most frequent cause of hyperekplexia (figure 4).
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| Figure 4. Associated residues in strychnine and ivermectin binding to GlyR |
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