8ugy

From Proteopedia

(Difference between revisions)

Current revision

Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin

Structural highlights

8ugy is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.31Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.^[1] ^[2]

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.

, PMID:38630816^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
↑ Zilberg G, Parpounas AK, Warren AL, Fiorillo B, Provasi D, Filizola M, Wacker D. Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT(1e)R and 5-HT(1F)R. Sci Adv. 2024 Apr 19;10(16):eadk4855. PMID:38630816 doi:10.1126/sciadv.adk4855

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8ugy"

Categories: Homo sapiens | Large Structures | Wacker D | Warren AL | Zilberg G

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8ugy is ON HOLD  until Paper Publication
+==Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin==
+<StructureSection load='8ugy' size='340' side='right'caption='[[8ugy]], [[Resolution|resolution]] 3.31&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8ugy]] is a 4 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=8UGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8UGY 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]] 3.31&#8491;</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=WRU:(5S,14bS)-2-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine'>WRU</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=8ugy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ugy OCA], [https://pdbe.org/8ugy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ugy RCSB], [https://www.ebi.ac.uk/pdbsum/8ugy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ugy ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/GNAI1_HUMAN GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.<ref>PMID:17635935</ref> <ref>PMID:17264214</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.
-Authors: Zilberg, G., Warren, A.L., Wacker, D.
+,  PMID:38630816<ref>PMID:38630816</ref>
-Description: Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Wacker, D]]
+<div class="pdbe-citations 8ugy" style="background-color:#fffaf0;"></div>
-[[Category: Warren, A.L]]
+== References ==
-[[Category: Zilberg, G]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Wacker D]]
+[[Category: Warren AL]]
+[[Category: Zilberg G]]

8ugy

From Proteopedia

Current revision

Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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