7T2G
CryoEM structure of mu-opioid receptor - Gi protein complex bound to mitragynine pseudoindoxyl (MP)
Summary for 7T2G
| Entry DOI | 10.2210/pdb7t2g/pdb |
| EMDB information | 25612 |
| Descriptor | Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total) |
| Functional Keywords | gpcr, mu-opioid receptor, lofentanil (lft), mitragynine pseudoindoxyl (mp), membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 142258.90 |
| Authors | Seven, A.B.,Qu, Q.,Robertson, M.J.,Wang, H.,Kobilka, B.K.,Skiniotis, G. (deposition date: 2021-12-04, release date: 2022-12-07, Last modification date: 2024-11-06) |
| Primary citation | Qu, Q.,Huang, W.,Aydin, D.,Paggi, J.M.,Seven, A.B.,Wang, H.,Chakraborty, S.,Che, T.,DiBerto, J.F.,Robertson, M.J.,Inoue, A.,Suomivuori, C.M.,Roth, B.L.,Majumdar, S.,Dror, R.O.,Kobilka, B.K.,Skiniotis, G. Insights into distinct signaling profiles of the mu OR activated by diverse agonists. Nat.Chem.Biol., 2022 Cited by PubMed Abstract: Drugs targeting the μ-opioid receptor (μOR) 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 μOR 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 β-arrestin recruitment. Cryo-EM structures of μOR-Gi1 complex with MP (2.5 Å) and LFT (3.2 Å) 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 β-arrestins bind. These observations highlight how drugs engaging different parts of the μOR orthosteric pocket can lead to distinct signaling outcomes. PubMed: 36411392DOI: 10.1038/s41589-022-01208-y PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.5 Å) |
Structure validation
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