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| | ==Structure of the human kappa opioid receptor in complex with JDTic== | | ==Structure of the human kappa opioid receptor in complex with JDTic== |
| - | <StructureSection load='4djh' size='340' side='right' caption='[[4djh]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4djh' size='340' side='right'caption='[[4djh]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4djh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DJH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DJH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4djh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DJH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DJH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=JDC:(3R)-7-HYDROXY-N-{(2S)-1-[(3R,4R)-4-(3-HYDROXYPHENYL)-3,4-DIMETHYLPIPERIDIN-1-YL]-3-METHYLBUTAN-2-YL}-1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXAMIDE'>JDC</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=JDC:(3R)-7-HYDROXY-N-{(2S)-1-[(3R,4R)-4-(3-HYDROXYPHENYL)-3,4-DIMETHYLPIPERIDIN-1-YL]-3-METHYLBUTAN-2-YL}-1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXAMIDE'>JDC</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">OPRK, OPRK1, OPRK, e ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4djh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4djh OCA], [https://pdbe.org/4djh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4djh RCSB], [https://www.ebi.ac.uk/pdbsum/4djh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4djh ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4djh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4djh OCA], [http://pdbe.org/4djh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4djh RCSB], [http://www.ebi.ac.uk/pdbsum/4djh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4djh ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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/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/ENLYS_BPT4 ENLYS_BPT4]] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| | *[[Lysozyme 3D structures|Lysozyme 3D structures]] | | *[[Lysozyme 3D structures|Lysozyme 3D structures]] |
| | + | *[[Opioid receptor|Opioid receptor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Escherichia virus T4]] |
| - | [[Category: Carroll, F I]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Cherezov, V]] | + | [[Category: Large Structures]] |
| - | [[Category: GPCR, GPCR Network]] | + | [[Category: Carroll FI]] |
| - | [[Category: Han, G W]] | + | [[Category: Cherezov V]] |
| - | [[Category: Huang, X P]] | + | [[Category: Han GW]] |
| - | [[Category: Katritch, V]] | + | [[Category: Huang XP]] |
| - | [[Category: Liu, W]] | + | [[Category: Katritch V]] |
| - | [[Category: Mascarella, S W]] | + | [[Category: Liu W]] |
| - | [[Category: Mileni, M]] | + | [[Category: Mascarella SW]] |
| - | [[Category: Mosier, P D]] | + | [[Category: Mileni M]] |
| - | [[Category: Roth, B L]] | + | [[Category: Mosier PD]] |
| - | [[Category: Stevens, R C]] | + | [[Category: Roth BL]] |
| - | [[Category: Thompson, A A]] | + | [[Category: Stevens RC]] |
| - | [[Category: Vardy, E]] | + | [[Category: Thompson AA]] |
| - | [[Category: Wacker, D]] | + | [[Category: Vardy E]] |
| - | [[Category: Westkaemper, R B]] | + | [[Category: Wacker D]] |
| - | [[Category: Wu, H]] | + | [[Category: Westkaemper RB]] |
| - | [[Category: Dynorphin]]
| + | [[Category: Wu H]] |
| - | [[Category: G-protein coupled receptor]]
| + | |
| - | [[Category: Gpcr]]
| + | |
| - | [[Category: Gpcr network]]
| + | |
| - | [[Category: Gpcr newtork]]
| + | |
| - | [[Category: Hkor]]
| + | |
| - | [[Category: Hormone receptor]]
| + | |
| - | [[Category: Hormone receptor-antagonist complex]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Jdtic]]
| + | |
| - | [[Category: Kappa opioid receptor]]
| + | |
| - | [[Category: Kop]]
| + | |
| - | [[Category: Kor]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: PSI, Protein structure initiative]]
| + | |
| - | [[Category: Psi-biology]]
| + | |
| - | [[Category: Structural genomic]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| Structural highlights
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] [ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[5]
Publication Abstract from PubMed
Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of kappa-opioid receptor (kappa-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR. Modelling of other important kappa-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR.
Structure of the human kappa-opioid receptor in complex with JDTic.,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 Nature. 2012 Mar 21;485(7398):327-32. doi: 10.1038/nature10939. PMID:22437504[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
- ↑ 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
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