8blb: Difference between revisions
No edit summary |
No edit summary |
||
| (One intermediate revision by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation)== | |||
<StructureSection load='8blb' size='340' side='right'caption='[[8blb]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8blb]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8BLB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BLB 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]] 3.3Å</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=8blb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8blb OCA], [https://pdbe.org/8blb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8blb RCSB], [https://www.ebi.ac.uk/pdbsum/8blb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8blb ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/5HT3A_HUMAN 5HT3A_HUMAN] Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.<ref>PMID:10521471</ref> <ref>PMID:12867984</ref> <ref>PMID:17392525</ref> <ref>PMID:9950429</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT(3) receptor (5-HT(3)R), which features two properties: VTX acts differently on rodent and human 5-HT(3)R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT(3)R and an agonist-bound-like state of human 5-HT(3)R, in line with the functional profile of the drug. We report four human 5-HT(3)R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism. | |||
Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT(3) receptors.,Lopez-Sanchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM, Baud D, Juillan-Binard C, Pedersen MG, Lummis SCR, Bang-Andersen B, Schiott B, Chipot C, Schoehn G, Neyton J, Dehez F, Nury H, Kristensen AS Nat Struct Mol Biol. 2024 May 2. doi: 10.1038/s41594-024-01282-x. PMID:38698207<ref>PMID:38698207</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8blb" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Lopez-Sanchez U]] | |||
[[Category: Nury H]] | |||
Latest revision as of 08:27, 28 August 2024
Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation)Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation)
Structural highlights
Function5HT3A_HUMAN Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.[1] [2] [3] [4] Publication Abstract from PubMedVortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT(3) receptor (5-HT(3)R), which features two properties: VTX acts differently on rodent and human 5-HT(3)R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT(3)R and an agonist-bound-like state of human 5-HT(3)R, in line with the functional profile of the drug. We report four human 5-HT(3)R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism. Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT(3) receptors.,Lopez-Sanchez U, Munro LJ, Ladefoged LK, Pedersen AJ, Brun CC, Lyngby SM, Baud D, Juillan-Binard C, Pedersen MG, Lummis SCR, Bang-Andersen B, Schiott B, Chipot C, Schoehn G, Neyton J, Dehez F, Nury H, Kristensen AS Nat Struct Mol Biol. 2024 May 2. doi: 10.1038/s41594-024-01282-x. PMID:38698207[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||