9O36
CryoEM structure of mu-opioid receptor - Gi protein complex bound to fluornitrazene (FNZ)
This is a non-PDB format compatible entry.
Summary for 9O36
| Entry DOI | 10.2210/pdb9o36/pdb |
| EMDB information | 70071 |
| 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, ... (6 entities in total) |
| Functional Keywords | complex, receptor, agonist, mor, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 162057.40 |
| Authors | Robertson, M.J.,Skiniotis, G. (deposition date: 2025-04-05, release date: 2026-04-01, Last modification date: 2026-05-13) |
| Primary citation | Gomez, J.L.,Ventriglia, E.N.,Frangos, Z.J.,Sulima, A.,Robertson, M.J.,Sacco, M.D.,Budinich, R.C.,Giosan, I.M.,Xie, T.,Solis, O.,Tischer, A.E.,Bossert, J.M.,Caldwell, K.E.,Bonbrest, H.,Essmann, A.,Garcon-Poca, Z.M.,Choi, S.,Noya, M.R.,Limiac, F.,Arce, A.,Glatfelter, G.C.,Robinson, M.,Chen, L.,Mullarkey, A.A.,Brademan, D.R.,Enten, G.,Dunne, W.,Quiroz, C.,Schoenborn, I.,Lee, C.B.,Rais, R.,Holt, D.P.,Dannals, R.F.,Shi, L.,Huttenhain, R.,Ferre, S.,Kiyatkin, E.,Bonaventura, J.,Shaham, Y.,Zachariou, V.,Baumann, M.H.,Skiniotis, G.,Rice, K.C.,Michaelides, M. A μ-opioid receptor superagonist analgesic with minimal adverse effects. Nature, 652:1393-1404, 2026 Cited by PubMed Abstract: Developing safe and effective pain medications is an ongoing challenge for human health. Agonists for the µ-opioid receptor (MOR) are essential pain medications, but their high intrinsic efficacy also induces adverse side effects, including respiratory depression, constipation, tolerance, dependence, withdrawal and addiction. Strategies to limit adverse effects traditionally include developing MOR agonists that have low intrinsic efficacy or that preferentially activate G-protein signalling over β-arrestin signalling. Here we identify a novel MOR agonist with supramaximal intrinsic efficacy and a unique pharmacological profile that produced effective analgesia in rodents with minimal adverse effects. N-desethyl-fluornitrazene (DFNZ) was derived from a class of synthetic benzimidazole opioids called nitazenes. DFNZ has impaired brain penetrance, a unique spatiotemporal MOR cellular signalling profile, and diminished efficacy at the MOR-galanin 1 receptor (GAL1) heteromer. DFNZ does not induce respiratory depression, tolerance or MOR downregulation after repeated exposure. Compared with other MOR agonists, DFNZ has limited effects on dopamine neurotransmission in nucleus accumbens and weaker reinforcing effects in the drug self-administration procedure. These results provide novel insights about MOR and nitazene pharmacology, have important implications for pain and addiction treatment, and challenge the prevailing dogma that high-efficacy MOR agonists cannot constitute safe and effective therapeutic agents. PubMed: 41922775DOI: 10.1038/s41586-026-10299-9 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.3 Å) |
Structure validation
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