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==Cryo-EM structure of 5HT3A receptor in presence of Alosetron== | ==Cryo-EM structure of 5HT3A receptor in presence of Alosetron== | ||
<StructureSection load='6w1j' size='340' side='right'caption='[[6w1j]]' scene=''> | <StructureSection load='6w1j' size='340' side='right'caption='[[6w1j]], [[Resolution|resolution]] 2.92Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W1J OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W1J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6W1J FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.92Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=S7Y:alosetron'>S7Y</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=6w1j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w1j OCA], [https://pdbe.org/6w1j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6w1j RCSB], [https://www.ebi.ac.uk/pdbsum/6w1j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6w1j ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition. | |||
High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition.,Basak S, Kumar A, Ramsey S, Gibbs E, Kapoor A, Filizola M, Chakrapani S Elife. 2020 Oct 16;9. pii: 57870. doi: 10.7554/eLife.57870. PMID:33063666<ref>PMID:33063666</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6w1j" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[5-hydroxytryptamine receptor 3D structures|5-hydroxytryptamine receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Latest revision as of 13:37, 23 October 2024
Cryo-EM structure of 5HT3A receptor in presence of AlosetronCryo-EM structure of 5HT3A receptor in presence of Alosetron
Structural highlights
Publication Abstract from PubMedSerotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition. High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition.,Basak S, Kumar A, Ramsey S, Gibbs E, Kapoor A, Filizola M, Chakrapani S Elife. 2020 Oct 16;9. pii: 57870. doi: 10.7554/eLife.57870. PMID:33063666[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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