7t2h: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7t2h]] is a 5 chain structure with sequence from [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=7T2H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T2H FirstGlance]. <br> | <table><tr><td colspan='2'>[[7t2h]] is a 5 chain structure with sequence from [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=7T2H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T2H FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EID: | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EID:methyl+(3~{R},4~{S})-3-methyl-1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate'>EID</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=7t2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t2h OCA], [https://pdbe.org/7t2h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t2h RCSB], [https://www.ebi.ac.uk/pdbsum/7t2h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t2h 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=7t2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t2h OCA], [https://pdbe.org/7t2h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t2h RCSB], [https://www.ebi.ac.uk/pdbsum/7t2h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t2h 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 7t2h" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7t2h" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Opioid receptor|Opioid receptor]] | |||
*[[Transducin 3D structures|Transducin 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 14:40, 30 October 2024
CryoEM structure of mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)CryoEM structure of mu-opioid receptor - Gi protein complex bound to lofentanil (LFT)
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedDrugs 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. 2023 Apr;19(4):423-430. doi: 10.1038/s41589-022-01208-y. Epub 2022 , Nov 21. PMID:36411392[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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