7ymj

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of alpha1AAR-Nb6 complex bound to tamsulosin

Structural highlights

7ymj is a 2 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.35Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OPRK_HUMAN G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.^[1] ^[2] ^[3] ^[4] ADA1A_HUMAN This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.^[5] ^[6]

Publication Abstract from PubMed

The alpha(1A-)adrenergic receptor (alpha(1A)AR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. alpha(1A)AR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human alpha(1A)AR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 A to 3.5 A. Our active and inactive alpha(1A)AR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of alpha(1A)AR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.

Structural basis of alpha(1A)-adrenergic receptor activation and recognition by an extracellular nanobody.,Toyoda Y, Zhu A, Kong F, Shan S, Zhao J, Wang N, Sun X, Zhang L, Yan C, Kobilka BK, Liu X Nat Commun. 2023 Jun 20;14(1):3655. doi: 10.1038/s41467-023-39310-x. PMID:37339967^[7]

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

References

↑ Li JG, Chen C, Liu-Chen LY. Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate. J Biol Chem. 2002 Jul 26;277(30):27545-52. Epub 2002 May 9. PMID:12004055 doi:http://dx.doi.org/10.1074/jbc.M200058200
↑ Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Structure of the human kappa-opioid receptor in complex with JDTic. Nature. 2012 Mar 21;485(7398):327-32. doi: 10.1038/nature10939. PMID:22437504 doi:10.1038/nature10939
↑ Simonin F, Gaveriaux-Ruff C, Befort K, Matthes H, Lannes B, Micheletti G, Mattei MG, Charron G, Bloch B, Kieffer B. kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7006-10. PMID:7624359
↑ Mansson E, Bare L, Yang D. Isolation of a human kappa opioid receptor cDNA from placenta. Biochem Biophys Res Commun. 1994 Aug 15;202(3):1431-7. PMID:8060324
↑ Wright CD, Chen Q, Baye NL, Huang Y, Healy CL, Kasinathan S, O'Connell TD. Nuclear alpha1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes. Circ Res. 2008 Oct 24;103(9):992-1000. PMID:18802028 doi:10.1161/CIRCRESAHA.108.176024
↑ Wright CD, Wu SC, Dahl EF, Sazama AJ, O'Connell TD. Nuclear localization drives α1-adrenergic receptor oligomerization and signaling in cardiac myocytes. Cell Signal. 2012 Mar;24(3):794-802. PMID:22120526 doi:10.1016/j.cellsig.2011.11.014
↑ Toyoda Y, Zhu A, Kong F, Shan S, Zhao J, Wang N, Sun X, Zhang L, Yan C, Kobilka BK, Liu X. Structural basis of α(1A)-adrenergic receptor activation and recognition by an extracellular nanobody. Nat Commun. 2023 Jun 20;14(1):3655. PMID:37339967 doi:10.1038/s41467-023-39310-x

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/7ymj"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[7ymj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7YMJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YMJ 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]] 3.35&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JGX:Tamsulosin'>JGX</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JGX:5-[(2~{R})-2-[2-(2-ethoxyphenoxy)ethylamino]propyl]-2-methoxy-benzenesulfonamide'>JGX</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=7ymj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ymj OCA], [https://pdbe.org/7ymj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ymj RCSB], [https://www.ebi.ac.uk/pdbsum/7ymj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ymj ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/OPRK_HUMAN OPRK_HUMAN] G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.<ref>PMID:12004055</ref> <ref>PMID:22437504</ref> <ref>PMID:7624359</ref> <ref>PMID:8060324</ref> [https://www.uniprot.org/uniprot/ADA1A_HUMAN ADA1A_HUMAN] This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.<ref>PMID:18802028</ref> <ref>PMID:22120526</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

7ymj

From Proteopedia

Current revision

Cryo-EM structure of alpha1AAR-Nb6 complex bound to tamsulosin

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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