View source for 6dzw


==Cryo-EM structure of the ts2-inactive human serotonin transporter in complex with paroxetine and 15B8 Fab and 8B6 ScFv==
<SX load='6dzw' size='340' side='right' viewer='molstar' caption='[[6dzw]], [[Resolution|resolution]] 4.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6dzw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DZW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8PR:PAROXETINE'>8PR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dzw OCA], [https://pdbe.org/6dzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dzw RCSB], [https://www.ebi.ac.uk/pdbsum/6dzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dzw ProSAT]</span></td></tr>
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== Function ==
[https://www.uniprot.org/uniprot/SC6A4_HUMAN SC6A4_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.<ref>PMID:17506858</ref> <ref>PMID:18227069</ref> <ref>PMID:19270731</ref> 
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== Publication Abstract from PubMed ==
The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons(1-3). Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors-small molecules that competitively block substrate binding and thereby prolong neurotransmitter action(2,4). The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines(2,3), and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder(2,5). Studies of bacterial NSS homologues-including LeuT-have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane(1,6-12). However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties(13,14). Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors(15,16). Here we report cryo-electron microscopy structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.

Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport.,Coleman JA, Yang D, Zhao Z, Wen PC, Yoshioka C, Tajkhorshid E, Gouaux E Nature. 2019 May;569(7754):141-145. doi: 10.1038/s41586-019-1135-1. Epub 2019 Apr, 24. PMID:31019304<ref>PMID:31019304</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6dzw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Antibody 3D structures|Antibody 3D structures]]
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
*[[Serotonin Transporter|Serotonin Transporter]]
*[[3D structures of non-human antibody|3D structures of non-human antibody]]
== References ==
<references/>
__TOC__
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Coleman JA]]
[[Category: Gouaux E]]
[[Category: Yang D]]