Ivermectin: Difference between revisions
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<StructureSection load='3rif' size='350' side='right' scene='' caption='Ivermectin bound to | <StructureSection load='3rif' size='350' side='right' scene='' caption='Ivermectin bound to Glu gated chloride channel (PDB ID [[3rif]])'> | ||
== Function == | == Function == | ||
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Ivermectin binds with high affinity to the glutamate-gated <scene name='75/756562/Chlorine/1'>chloride</scene> channels that reside in invertebrate nerve and muscle cells <ref name="Stanford">Stanford Edu. Mechanism of Action. ParaSites2005. Retrieved from https://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/mechanism%20of%20action.htm</ref>. In contrast to most <scene name='75/756562/Chloride_channel/1'>glutamate-gated chloride channels</scene>, where binding of the ligand and the subsequent activation of the channel is permitted in the absence of the drug, Glutamate only binds to the homomeric GLC-1 receptor in the presence of a bound Ivermectin molecule. The ivermectin-binding site is located in the channel domain situated between the M3 and M1 membrane spanning domains of two adjacent subunits, where Ivermectin, in close proximity to the M2 spanning domain that extends throughout the interior of the ion channel, establishes contact with the M2 domain and the M2-M3 loop. The overlapping of the ivermectin-binding site and the binding sites of volatile drugs and anesthetics that operate at mammalian GABA and glycine receptors, indicates that Ivermectin binding to this site may induce conformational alterations to the glutamate-binding site as a result of Ivermectin’s interaction with the M2-M3 loop. These conformational adaptations could engender allosteric modifications in structure, and Ivermectin’s interactions with M2 residues may secure the channel in the long-lasting open configuration that is distinctive of the binding arrangements associated with these drugs. Although the highly cooperative nature of the glutamate responses propose that multiple bound Ivermectin molecules are required to open the channel, or potentiate the glutamate response, it is not specifically known how many Ivermectin molecules are needed to initiate these responses. However, the slow opening of the channel is a mechanistic consequence that can be attributed to Ivermectin binding at the overlapping site <ref name="wol">Wolstenholme, A. J. (2012). Glutamate-gated Chloride Channels. The Journal of Biological Chemistry, 287(48), 40232–40238. http://doi.org/10.1074/jbc.R112.406280.</ref> | Ivermectin binds with high affinity to the glutamate-gated <scene name='75/756562/Chlorine/1'>chloride</scene> channels that reside in invertebrate nerve and muscle cells <ref name="Stanford">Stanford Edu. Mechanism of Action. ParaSites2005. Retrieved from https://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/mechanism%20of%20action.htm</ref>. In contrast to most <scene name='75/756562/Chloride_channel/1'>glutamate-gated chloride channels</scene>, where binding of the ligand and the subsequent activation of the channel is permitted in the absence of the drug, Glutamate only binds to the homomeric GLC-1 receptor in the presence of a bound Ivermectin molecule. The ivermectin-binding site is located in the channel domain situated between the M3 and M1 membrane spanning domains of two adjacent subunits, where Ivermectin, in close proximity to the M2 spanning domain that extends throughout the interior of the ion channel, establishes contact with the M2 domain and the M2-M3 loop. The overlapping of the ivermectin-binding site and the binding sites of volatile drugs and anesthetics that operate at mammalian GABA and glycine receptors, indicates that Ivermectin binding to this site may induce conformational alterations to the glutamate-binding site as a result of Ivermectin’s interaction with the M2-M3 loop. These conformational adaptations could engender allosteric modifications in structure, and Ivermectin’s interactions with M2 residues may secure the channel in the long-lasting open configuration that is distinctive of the binding arrangements associated with these drugs. Although the highly cooperative nature of the glutamate responses propose that multiple bound Ivermectin molecules are required to open the channel, or potentiate the glutamate response, it is not specifically known how many Ivermectin molecules are needed to initiate these responses. However, the slow opening of the channel is a mechanistic consequence that can be attributed to Ivermectin binding at the overlapping site <ref name="wol">Wolstenholme, A. J. (2012). Glutamate-gated Chloride Channels. The Journal of Biological Chemistry, 287(48), 40232–40238. http://doi.org/10.1074/jbc.R112.406280.</ref> | ||
[[Image:Ivermectin binding 3rif.jpg]] | [[Image:Ivermectin binding 3rif.jpg|400px]] | ||
'''Figure 2''' Ivermectin binds between the membrane-spanning domains, M1 and M3, of two adjacent subunits, typically pushing the membrane-spanning regions of the subunits in opposite directions, and thus, initiating the opening of the channel. The transmittance of allosteric signals to the ligand-binding site is engendered by Ivermectin’s contact with the M2-M3 loop and other regions of the extracellular domain. <ref name="wol" /> | '''Figure 2''' Ivermectin binds between the membrane-spanning domains, M1 and M3, of two adjacent subunits, typically pushing the membrane-spanning regions of the subunits in opposite directions, and thus, initiating the opening of the channel. The transmittance of allosteric signals to the ligand-binding site is engendered by Ivermectin’s contact with the M2-M3 loop and other regions of the extracellular domain. <ref name="wol" /> | ||
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</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||