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Figure 2 | Ion channel pore size when strychnine is bound. At Leu277, the distances between the helices is about 8Å; at Pro266, the distances between helices is about 7.2Å.
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| Figure 3 | Ion channel pore size when glycine is bound. At Leu277, the distances between the helices is about 10.9Å; at Pro266, the distances between helices is about 9 Å. |
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| Figure 4 | Ion channel pore size when ivermectin is bound. At Leu277, the distances between the helices is about 6.8Å; at Pro266, the distances between helices is about 10.6 Å. |
The ion channel pore consists of 5 alpha helices. When strychnine is bound to the receptor, the ion channel pore is closed and vice versa when glycine is bound to the receptor. When glycine/ivermectin is bound, the pore is in a partially open state. There are 2 sites of constriction on each alpha helix; a proline residue (Pro266) and a leucine residue (Leu277). In the closed state, the proline and leucine side chains are directed towards the inside of the channel. In the open state, the side chains of the amino acid residues are rotated sideways.
NEUROTRANSMITTER-BINDING SITE
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| Figure 5 | Strychnine affects the conformation of the receptor compared to when glycine is bound. |
Both glycine and strychnine bind to the neurotransmitter-binding site of the receptor, with strychnine acting as a competitive antagonist. The binding site is located behind the C loop (Y218 - T220), with the C loop covering the binding site. Furthermore, the conformation of the C loop changes depending on whether the antagonist (strychnine) or the agonist (glycine) is bound. When the glycine receptor is closed, meaning that the antagonist is bound, the C loop adopts an “open” conformation. However, when the receptor is open, the C loop adopts a “closed” conformation.
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Figure 6 | Figure 6 shows the difference in C-loop structure depending on whether strychnine or glycine is bound.
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ALLOSTERIC BINDING SITE
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Figure 7 | Figure 7 shows the ivermectin binding site. Residues S294, R287 and S283 on the M2 helix form hydrogen bonds with the ivermectin molecule, changing the conformation of the overall glycine receptor structure.
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Ivermectin is an allosteric modulator, which is a molecule that binds allosterically, causing a conformational change that increases the affinity for glycine. This means that it binds at a separate site from the glycine and strychnine binding site. Ivermectin (orange) interacts with the M2 helix, forming hydrogen bonds with R287 (pink), S283 (cyan) and S294 (red).
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