Summary for 9BQJ
| Entry DOI | 10.2210/pdb9bqj/pdb |
| EMDB information | 44812 |
| Descriptor | 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, Mu-type opioid receptor, ... (7 entities in total) |
| Functional Keywords | gpcr, g protein, opioid receptor, signaling protein-immune system complex, signaling protein/immune system |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 154107.80 |
| Authors | Wang, H.,Majumdar, S.,Kobilka, B.K. (deposition date: 2024-05-10, release date: 2024-09-11, Last modification date: 2025-05-21) |
| Primary citation | Ople, R.S.,Ramos-Gonzalez, N.,Li, Q.,Sobecks, B.L.,Aydin, D.,Powers, A.S.,Faouzi, A.,Polacco, B.J.,Bernhard, S.M.,Appourchaux, K.,Sribhashyam, S.,Eans, S.O.,Tsai, B.A.,Dror, R.O.,Varga, B.R.,Wang, H.,Huttenhain, R.,McLaughlin, J.P.,Majumdar, S. Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at mu OR. Acs Cent.Sci., 10:1490-1503, 2024 Cited by PubMed Abstract: The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named . Presently, to improve systemic activity of this ligand, we used structure-based design, identifying a new ligand named where the flexible alkyl linker and polar guanidine guano group is swapped with a benzyl alcohol, and the sodium site is targeted indirectly through waters. A cryoEM structure of bound to the μOR-G complex confirmed that interacts with the sodium site residues through a water molecule, unlike which engages the sodium site directly. Signaling assays coupled with APEX based proximity labeling show binding in the sodium pocket modulates receptor efficacy and trafficking. In mice, was systemically active in tail withdrawal assays and showed reduced liabilities compared to those of morphine. In summary, we show that targeting water molecules in the sodium binding pocket may be an avenue to modulate signaling properties of opioids, and which may potentially be extended to other G-protein coupled receptors where this site is conserved. PubMed: 39220695DOI: 10.1021/acscentsci.4c00525 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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