8uh3: Difference between revisions
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<table><tr><td colspan='2'>[[8uh3]] is a 5 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=8UH3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UH3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8uh3]] is a 5 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=8UH3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UH3 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]] 3.31Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.31Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=WOQ: | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=WOQ:[4a(13b)M,13aM]-2-methyl-2,3,4,9-tetrahydro-1H-dibenzo[3,4 6,7]cyclohepta[1,2-c]pyridine'>WOQ</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=8uh3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uh3 OCA], [https://pdbe.org/8uh3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uh3 RCSB], [https://www.ebi.ac.uk/pdbsum/8uh3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uh3 ProSAT]</span></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=8uh3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8uh3 OCA], [https://pdbe.org/8uh3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8uh3 RCSB], [https://www.ebi.ac.uk/pdbsum/8uh3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8uh3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref> | [https://www.uniprot.org/uniprot/GBB1_HUMAN GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.<ref>PMID:18611381</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT(1e)R's pharmacology in relation to the highly homologous 5-HT(1F)R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT(1e)R/5-HT(1F)R agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT(1e)R distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT(1e)R and 5-HT(1F)R contribute to the agonist activity of these antidepressants. | |||
Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT(1e)R and 5-HT(1F)R.,Zilberg G, Parpounas AK, Warren AL, Fiorillo B, Provasi D, Filizola M, Wacker D Sci Adv. 2024 Apr 19;10(16):eadk4855. doi: 10.1126/sciadv.adk4855. Epub 2024 Apr , 17. PMID:38630816<ref>PMID:38630816</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8uh3" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 15:12, 30 October 2024
Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with SetiptilineSerotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Setiptiline
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedSerotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT(1e)R's pharmacology in relation to the highly homologous 5-HT(1F)R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT(1e)R/5-HT(1F)R agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT(1e)R distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT(1e)R and 5-HT(1F)R contribute to the agonist activity of these antidepressants. Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT(1e)R and 5-HT(1F)R.,Zilberg G, Parpounas AK, Warren AL, Fiorillo B, Provasi D, Filizola M, Wacker D Sci Adv. 2024 Apr 19;10(16):eadk4855. doi: 10.1126/sciadv.adk4855. Epub 2024 Apr , 17. PMID:38630816[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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