Serotonin Transporter: Difference between revisions
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====Pharmaceutical Implications==== | ====Pharmaceutical Implications==== | ||
Tricyclic antidepressants (TCAs) were among the first antidepressants ever developed. Discovered in the 1950s, they are named after their unique structure which contains three rings. One of the best known TCAs, <scene name='Serotonin_Transporter/Chlomipramine/1'>chlomipramine</scene>, developed by Novartis, inhibits SERTs with remarkable efficacy. Chlomipramine binds at the <scene name='Serotonin_Transporter/Chlomipramine_top/1'>entry way of the serotonin pore</scene> It forms a <scene name='Serotonin_Transporter/Chlomipramine_bound/1'>number of interactions</scene> which hold the molecule in place, completely occluding the pore. One particularly unique interaction involves a <scene name='Serotonin_Transporter/Chlomipramine_bound/2'>Chlomipramine-Arg-Phe</scene> sandwhich involving residues Arg 30 and Phe 253. As mentioned before, this structure is of LeuT and not a SERT, but the structures have significant homology. The structure reveals how Chlomipramine inhibits reuptake. | Tricyclic antidepressants (TCAs) were among the first antidepressants ever developed. Discovered in the 1950s, they are named after their unique structure which contains three rings. One of the best known TCAs, <scene name='Serotonin_Transporter/Chlomipramine/1'>chlomipramine</scene>, developed by Novartis, inhibits SERTs with remarkable efficacy. Chlomipramine binds at the <scene name='Serotonin_Transporter/Chlomipramine_top/1'>entry way of the serotonin pore</scene> It forms a <scene name='Serotonin_Transporter/Chlomipramine_bound/1'>number of interactions</scene> which hold the molecule in place, completely occluding the pore. One particularly unique interaction involves a <scene name='Serotonin_Transporter/Chlomipramine_bound/2'>Chlomipramine-Arg-Phe</scene> sandwhich involving residues Arg 30 and Phe 253. As mentioned before, this structure is of LeuT and not a SERT, but the structures have significant homology. The structure reveals how Chlomipramine inhibits reuptake. <scene name='Serotonin_Transporter/Chlomipramine_top/2'>Chlomipramine binds to the pore</scene>, but also, the closed pore conformation is stabilized by also <scene name='Serotonin_Transporter/Bound_sub/1'>binding its native ligand</scene>, which in this case is leucine, but in the case of a SERT, would be serotonin. The Leucine molecule is bound below the inhibitor and is <scene name='Serotonin_Transporter/Bound_sub/2'>stabilized by a number of interactions</scene>. Typically, a second leucine would likely bind in the Chlomipramine binding pocket, resulting in leucine release in the presynaptic space.<ref>PMID:17687333</ref> | ||
SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of [[autism]] by preventing **SERT function**. Two well-known SSRIs, Sertraline (Zoloft) and fluoxetine (Prozac) bind in nearly the **same location as chlomipramine SERTRALINE**. They are stabilized by a **number of interactions** with the SERT structure. Interestingly, both of these second generation antidepressants contain halogenated subgroups which interact in very specific ways with the transporter structure. In the case of sertraline, the chlorine atoms on the phenyl ring insert into a pocket dubbed the halogen binding pocket (HBP). This pocket consists of residues Leu 25, Gly 26, Leu 29, Arg 30, Tyr 108, Ile 111, and Phe 253. Several of these residues, Leu 25, Gly 26, Tyr 108, and Phe 253 are also involved in **binding the substrate** Leucine. The binding of Fluoxetine is** nearly identical** involving nearly all of the same residues.<ref>PMID:19430461</ref> | SSRIs are a second generation of very powerful antidepressants used to treat depression, anxiety disorders, and recently symptoms of [[autism]] by preventing **SERT function**. Two well-known SSRIs, Sertraline (Zoloft) and fluoxetine (Prozac) bind in nearly the **same location as chlomipramine SERTRALINE**. They are stabilized by a **number of interactions** with the SERT structure. Interestingly, both of these second generation antidepressants contain halogenated subgroups which interact in very specific ways with the transporter structure. In the case of sertraline, the chlorine atoms on the phenyl ring insert into a pocket dubbed the halogen binding pocket (HBP). This pocket consists of residues Leu 25, Gly 26, Leu 29, Arg 30, Tyr 108, Ile 111, and Phe 253. Several of these residues, Leu 25, Gly 26, Tyr 108, and Phe 253 are also involved in **binding the substrate** Leucine. The binding of Fluoxetine is** nearly identical** involving nearly all of the same residues.<ref>PMID:19430461</ref> | ||