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-Structure paper
タイトル | Structure-Based Evolution of G Protein-Biased μ-Opioid Receptor Agonists. |
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ジャーナル・号・ページ | Angew Chem Int Ed Engl, Vol. 61, Issue 26, Page e202200269, Year 2022 |
掲載日 | 2022年6月27日 |
![]() | Haoqing Wang / Florian Hetzer / Weijiao Huang / Qianhui Qu / Justin Meyerowitz / Jonas Kaindl / Harald Hübner / Georgios Skiniotis / Brian K Kobilka / Peter Gmeiner / ![]() ![]() ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 2.9 - 3.0 Å |
構造データ | EMDB-24978, PDB-7sbf: EMDB-25034, PDB-7scg: |
化合物 | ![]() ChemComp-8QY: ![]() ChemComp-8RI: ![]() ChemComp-HOH: |
由来 |
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![]() | MEMBRANE PROTEIN / GPCR |