8e0g

From Proteopedia

(Difference between revisions)

Current revision

Re-refined model of active mu-opioid receptor (PDB 5c1m) as an adduct with BU72

Structural highlights

8e0g is a 2 chain structure with sequence from Lama glama and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OPRM_MOUSE Receptor for endogenous opioids such as beta-endorphin and endomorphin. Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors. The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extend to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15. They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B. Also couples to adenylate cyclase stimulatory G alpha proteins. The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4. Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization. Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction. The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins. The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation. Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling. Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling. Endogenous ligands induce rapid desensitization, endocytosis and recycling. Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties. Involved in neurogenesis. Isoform 9 is involved in morphine-induced scratching and seems to cross-activate GRPR in response to morphine.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

BACKGROUND: The first crystal structure of the active mu opioid receptor (muOR) exhibited several unexplained features. The ligand BU72 exhibited many extreme deviations from ideal geometry, along with unexplained electron density. I previously showed that inverting the benzylic configuration resolved these problems, establishing revised stereochemistry of BU72 and its analog BU74. However, another problem remains unresolved: additional unexplained electron density contacts both BU72 and a histidine residue in the N-terminus, revealing the presence of an as-yet unidentified atom. RESULTS: These short contacts and uninterrupted density are inconsistent with non-covalent interactions. Therefore, BU72 and muOR form a covalent adduct, rather than representing two separate entities as in the original model. A subsequently proposed magnesium complex is inconsistent with multiple lines of evidence. However, oxygen fits the unexplained density well. While the structure I propose is tentative, similar adducts have been reported previously in the presence of reactive oxygen species. Moreover, known sources of reactive oxygen species were present: HEPES buffer, nickel ions, and a sequence motif that forms redox-active nickel complexes. This motif contacts the unexplained density. The adduct exhibits severe strain, and the tethered N-terminus forms contacts with adjacent residues. These forces, along with the nanobody used as a G protein substitute, would be expected to influence the receptor conformation. Consistent with this, the intracellular end of the structure differs markedly from subsequent structures of active muOR bound to G(i) protein. CONCLUSIONS: Later G(i)-bound structures are likely to be more accurate templates for ligand docking and modelling of active G protein-bound muOR. The possibility of reactions like this should be considered in the choice of protein truncation sites and purification conditions, and in the interpretation of excess or unexplained density.

Reanalysis of a mu opioid receptor crystal structure reveals a covalent adduct with BU72.,Munro TA BMC Biol. 2023 Oct 10;21(1):213. doi: 10.1186/s12915-023-01689-w. PMID:37817141^[7]

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

References

↑ George SR, Fan T, Xie Z, Tse R, Tam V, Varghese G, O'Dowd BF. Oligomerization of mu- and delta-opioid receptors. Generation of novel functional properties. J Biol Chem. 2000 Aug 25;275(34):26128-35. PMID:10842167 doi:http://dx.doi.org/10.1074/jbc.M000345200
↑ Rios C, Gomes I, Devi LA. mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol. 2006 Jun;148(4):387-95. Epub 2006 May 8. PMID:16682964 doi:http://dx.doi.org/10.1038/sj.bjp.0706757
↑ Milan-Lobo L, Whistler JL. Heteromerization of the mu- and delta-opioid receptors produces ligand-biased antagonism and alters mu-receptor trafficking. J Pharmacol Exp Ther. 2011 Jun;337(3):868-75. doi: 10.1124/jpet.111.179093. Epub , 2011 Mar 21. PMID:21422164 doi:http://dx.doi.org/10.1124/jpet.111.179093
↑ Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature. 2012 Mar 21. doi: 10.1038/nature10954. PMID:22437502 doi:10.1038/nature10954
↑ Kaufman DL, Keith DE Jr, Anton B, Tian J, Magendzo K, Newman D, Tran TH, Lee DS, Wen C, Xia YR, et al.. Characterization of the murine mu opioid receptor gene. J Biol Chem. 1995 Jun 30;270(26):15877-83. PMID:7797593
↑ Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, Miner LL, Uhl GR. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1544-9. PMID:9037090
↑ Munro TA. Reanalysis of a μ opioid receptor crystal structure reveals a covalent adduct with BU72. BMC Biol. 2023 Oct 10;21(1):213. PMID:37817141 doi:10.1186/s12915-023-01689-w

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

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OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8e0g"

Categories: Lama glama | Large Structures | Mus musculus | Munro TA

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[8e0g]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lama_glama Lama glama] 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=8E0G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E0G FirstGlance]. <br>
 </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#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=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=U8S:3-[(2S)-2-hydroxy-2,3-dihydro-1H-imidazol-4-yl]-L-alanine'>U8S</scene>, <scene name='pdbligand=VF1:(2R,3S,3aR,5aR,6R,11bR,11cS)-3a-methoxy-3,14-dimethyl-2-phenyl-2,3,3a,6,7,11c-hexahydro-1H-6,11b-(epiminoethano)-3,5a-methanonaphtho[2,1-g]indol-10-ol'>VF1</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1A7R:(2R,3S,3aR,5aS,6R,11bR,11cS)-3a-methoxy-3,14-dimethyl-2-phenyl-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-3,5a-methanonaphtho[2,1-g]indole-1,10-diol'>A1A7R</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=YCM:S-(2-AMINO-2-OXOETHYL)-L-CYSTEINE'>YCM</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=8e0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e0g OCA], [https://pdbe.org/8e0g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e0g RCSB], [https://www.ebi.ac.uk/pdbsum/8e0g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e0g ProSAT]</span></td></tr>
 </table>

8e0g

From Proteopedia

Current revision

Re-refined model of active mu-opioid receptor (PDB 5c1m) as an adduct with BU72

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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