7SBF
PZM21 bound Mu Opioid Receptor-Gi Protein Complex
Summary for 7SBF
| Entry DOI | 10.2210/pdb7sbf/pdb |
| EMDB information | 24978 |
| 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 | gpcr, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 169217.50 |
| Authors | Huang, W.,Qu, Q.,Wang, H.,Skiniotis, G.,Kobilka, B. (deposition date: 2021-09-24, release date: 2022-04-20, Last modification date: 2025-05-28) |
| Primary citation | Wang, H.,Hetzer, F.,Huang, W.,Qu, Q.,Meyerowitz, J.,Kaindl, J.,Hubner, H.,Skiniotis, G.,Kobilka, B.K.,Gmeiner, P. Structure-Based Evolution of G Protein-Biased mu-Opioid Receptor Agonists. Angew.Chem.Int.Ed.Engl., 61:e202200269-e202200269, 2022 Cited by PubMed Abstract: The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with G protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced G protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with G protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce β-arrestin recruitment by the μOR, and hold promise for developing next-generation analgesics with fewer adverse effects. PubMed: 35385593DOI: 10.1002/anie.202200269 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.9 Å) |
Structure validation
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