6w2c
From Proteopedia
Anomalous iodine signal reveals the position of I-paroxetine complexed with the serotonin transporter at the central site
Structural highlights
FunctionSC6A4_HUMAN Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into the pre-synaptic terminal for re-utilization. Plays a key role in mediating regulation of the availability of serotonin to other receptors of serotonergic systems. Terminates the action of serotonin and recycles it in a sodium-dependent manner.[1] [2] [3] Publication Abstract from PubMedAntidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation and inhibitor binding poses of wild-type transporter. To address these concerns, we determined the structures of N72/C13 and ts2-inactive SERT bound to paroxetine analogues using single-particle cryo-EM and x-ray crystallography, respectively. We synthesized enantiopure analogues of paroxetine containing either bromine or iodine instead of fluorine. We exploited the anomalous scattering of bromine and iodine to define the pose of these inhibitors and investigated inhibitor binding to Asn177 mutants of ts2-active SERT. These studies provide mutually consistent insights into how paroxetine and its analogues bind to the central substrate-binding site of SERT, stabilize the outward-open conformation, and inhibit serotonin transport. Chemical and structural investigation of the paroxetine-human serotonin transporter complex.,Coleman JA, Navratna V, Antermite D, Yang D, Bull JA, Gouaux E Elife. 2020 Jul 3;9. pii: 56427. doi: 10.7554/eLife.56427. PMID:32618269[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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