7t2g
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7t2g]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7T2G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T2G FirstGlance]. <br> | <table><tr><td colspan='2'>[[7t2g]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] 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=7T2G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T2G FirstGlance]. <br> | ||
| - | </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=EIG: | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.5Å</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=EIG:methyl+(~{E})-2-[(2~{S},8~{a}~{S})-6-ethyl-4-methoxy-3-oxidanylidene-spiro[1~{H}-indole-2,1-3,5,6,7,8,8~{a}-hexahydro-2~{H}-indolizine]-7-yl]-3-methoxy-prop-2-enoate'>EIG</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=7t2g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t2g OCA], [https://pdbe.org/7t2g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t2g RCSB], [https://www.ebi.ac.uk/pdbsum/7t2g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t2g ProSAT]</span></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=7t2g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t2g OCA], [https://pdbe.org/7t2g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t2g RCSB], [https://www.ebi.ac.uk/pdbsum/7t2g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t2g ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Drugs targeting the mu-opioid receptor (muOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two muOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and beta-arrestin recruitment. Cryo-EM structures of muOR-Gi1 complex with MP (2.5 A) and LFT (3.2 A) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and beta-arrestins bind. These observations highlight how drugs engaging different parts of the muOR orthosteric pocket can lead to distinct signaling outcomes. | Drugs targeting the mu-opioid receptor (muOR) are the most effective analgesics available but are also associated with fatal respiratory depression through a pathway that remains unclear. Here we investigated the mechanistic basis of action of lofentanil (LFT) and mitragynine pseudoindoxyl (MP), two muOR agonists with different safety profiles. LFT, one of the most lethal opioids, and MP, a kratom plant derivative with reduced respiratory depression in animal studies, exhibited markedly different efficacy profiles for G protein subtype activation and beta-arrestin recruitment. Cryo-EM structures of muOR-Gi1 complex with MP (2.5 A) and LFT (3.2 A) revealed that the two ligands engage distinct subpockets, and molecular dynamics simulations showed additional differences in the binding site that promote distinct active-state conformations on the intracellular side of the receptor where G proteins and beta-arrestins bind. These observations highlight how drugs engaging different parts of the muOR orthosteric pocket can lead to distinct signaling outcomes. | ||
| - | Insights into distinct signaling profiles of the microOR activated by diverse agonists.,Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, Chakraborty S, Che T, DiBerto JF, Robertson MJ, Inoue A, Suomivuori CM, Roth BL, Majumdar S, Dror RO, Kobilka BK, Skiniotis G Nat Chem Biol. | + | Insights into distinct signaling profiles of the microOR activated by diverse agonists.,Qu Q, Huang W, Aydin D, Paggi JM, Seven AB, Wang H, Chakraborty S, Che T, DiBerto JF, Robertson MJ, Inoue A, Suomivuori CM, Roth BL, Majumdar S, Dror RO, Kobilka BK, Skiniotis G Nat Chem Biol. 2023 Apr;19(4):423-430. doi: 10.1038/s41589-022-01208-y. Epub 2022 , Nov 21. PMID:36411392<ref>PMID:36411392</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7t2g" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7t2g" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Opioid receptor|Opioid receptor]] | ||
| + | *[[Transducin 3D structures|Transducin 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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[[Category: Robertson MJ]] | [[Category: Robertson MJ]] | ||
[[Category: Seven AB]] | [[Category: Seven AB]] | ||
| + | [[Category: Skiniotis G]] | ||
[[Category: Wang H]] | [[Category: Wang H]] | ||
Current revision
CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP)
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