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6pt3

From Proteopedia

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Current revision

Crystal structure of the active delta opioid receptor in complex with the small molecule agonist DPI-287

Structural highlights

6pt3 is a 2 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:	X-ray diffraction, Resolution 3.3Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OPRD_HUMAN G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. 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 and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Selective activation of the delta-opioid receptor (DOP) has great potential for the treatment of chronic pain, benefitting from ancillary anxiolytic and antidepressant-like effects. Moreover, DOP agonists show reduced adverse effects as compared to mu-opioid receptor (MOP) agonists that are in the spotlight of the current "opioid crisis." Here, we report the first crystal structures of the DOP in an activated state, in complex with two relevant and structurally diverse agonists: the potent opioid agonist peptide KGCHM07 and the small-molecule agonist DPI-287 at 2.8 and 3.3 A resolution, respectively. Our study identifies key determinants for agonist recognition, receptor activation, and DOP selectivity, revealing crucial differences between both agonist scaffolds. Our findings provide the first investigation into atomic-scale agonist binding at the DOP, supported by site-directed mutagenesis and pharmacological characterization. These structures will underpin the future structure-based development of DOP agonists for an improved pain treatment with fewer adverse effects.

Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists.,Claff T, Yu J, Blais V, Patel N, Martin C, Wu L, Han GW, Holleran BJ, Van der Poorten O, White KL, Hanson MA, Sarret P, Gendron L, Cherezov V, Katritch V, Ballet S, Liu ZJ, Muller CE, Stevens RC Sci Adv. 2019 Nov 27;5(11):eaax9115. doi: 10.1126/sciadv.aax9115. eCollection, 2019 Nov. PMID:31807708^[4]

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

References

↑ Leskela TT, Lackman JJ, Vierimaa MM, Kobayashi H, Bouvier M, Petaja-Repo UE. Cys-27 variant of human delta-opioid receptor modulates maturation and cell surface delivery of Phe-27 variant via heteromerization. J Biol Chem. 2012 Feb 10;287(7):5008-20. doi: 10.1074/jbc.M111.305656. Epub 2011 , Dec 19. PMID:22184124 doi:http://dx.doi.org/10.1074/jbc.M111.305656
↑ Simonin F, Befort K, Gaveriaux-Ruff C, Matthes H, Nappey V, Lannes B, Micheletti G, Kieffer B. The human delta-opioid receptor: genomic organization, cDNA cloning, functional expression, and distribution in human brain. Mol Pharmacol. 1994 Dec;46(6):1015-21. PMID:7808419
↑ Knapp RJ, Malatynska E, Fang L, Li X, Babin E, Nguyen M, Santoro G, Varga EV, Hruby VJ, Roeske WR, et al.. Identification of a human delta opioid receptor: cloning and expression. Life Sci. 1994;54(25):PL463-9. PMID:8201839
↑ Claff T, Yu J, Blais V, Patel N, Martin C, Wu L, Han GW, Holleran BJ, Van der Poorten O, White KL, Hanson MA, Sarret P, Gendron L, Cherezov V, Katritch V, Ballet S, Liu ZJ, Muller CE, Stevens RC. Elucidating the active delta-opioid receptor crystal structure with peptide and small-molecule agonists. Sci Adv. 2019 Nov 27;5(11):eaax9115. doi: 10.1126/sciadv.aax9115. eCollection, 2019 Nov. PMID:31807708 doi:http://dx.doi.org/10.1126/sciadv.aax9115

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6pt3"

@@ Line 3: / Line 3: @@
 <StructureSection load='6pt3' size='340' side='right'caption='[[6pt3]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pt3]] 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=6PT3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PT3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pt3]] is a 2 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=6PT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PT3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OWY:4-[(R)-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl](3-hydroxyphenyl)methyl]-N,N-diethylbenzamide'>OWY</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3&#8491;</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=6pt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pt3 OCA], [http://pdbe.org/6pt3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pt3 RCSB], [http://www.ebi.ac.uk/pdbsum/6pt3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pt3 ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OWY:4-[(R)-[(2S,5R)-4-benzyl-2,5-dimethylpiperazin-1-yl](3-hydroxyphenyl)methyl]-N,N-diethylbenzamide'>OWY</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=6pt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pt3 OCA], [https://pdbe.org/6pt3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pt3 RCSB], [https://www.ebi.ac.uk/pdbsum/6pt3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pt3 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/OPRD_HUMAN OPRD_HUMAN] G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. 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 and in opiate-mediated analgesia. Plays a role in developing analgesic tolerance to morphine.<ref>PMID:22184124</ref> <ref>PMID:7808419</ref> <ref>PMID:8201839</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 16: / Line 19: @@
 </div>
 <div class="pdbe-citations 6pt3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Opioid receptor|Opioid receptor]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ballet, S]]
+[[Category: Ballet S]]
-[[Category: Blais, V]]
+[[Category: Blais V]]
-[[Category: Cherezov, V]]
+[[Category: Cherezov V]]
-[[Category: Claff, T]]
+[[Category: Claff T]]
-[[Category: Gendron, L]]
+[[Category: Gendron L]]
-[[Category: Han, G W]]
+[[Category: Han GW]]
-[[Category: Hanson, M A]]
+[[Category: Hanson MA]]
-[[Category: Holleran, B J]]
+[[Category: Holleran BJ]]
-[[Category: Katritch, V]]
+[[Category: Katritch V]]
-[[Category: Liu, Z]]
+[[Category: Liu Z]]
-[[Category: Martin, C]]
+[[Category: Martin C]]
-[[Category: Muller, C E]]
+[[Category: Muller CE]]
-[[Category: Patel, N]]
+[[Category: Patel N]]
-[[Category: Poorten, O Van der]]
+[[Category: Sarret P]]
-[[Category: Sarret, P]]
+[[Category: Stevens RC]]
-[[Category: Stevens, R C]]
+[[Category: Van der Poorten O]]
-[[Category: Wu, L]]
+[[Category: Wu L]]
-[[Category: Yu, J]]
+[[Category: Yu J]]
-[[Category: Active dop-dpi-287 structure]]
-[[Category: Agonist]]
-[[Category: Dop]]
-[[Category: Dor]]
-[[Category: G protein-coupled receptor]]
-[[Category: Gpcr]]
-[[Category: Lcp]]
-[[Category: Membrane protein]]
-[[Category: Membrane protein-agonist complex]]

6pt3

From Proteopedia

Current revision

Crystal structure of the active delta opioid receptor in complex with the small molecule agonist DPI-287

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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