7w7e

Cryo-EM structure of the alpha2A adrenergic receptor GoA signaling complex bound to a biased agonist

spinqualitylabelsall models 7w7e, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7w7e is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.4Å Ligands: W58 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the alpha(2A)-adrenergic receptor (alpha(2A)AR), seeking new alpha(2A)AR agonists chemotypes that lack the sedation conferred by known alpha(2A)AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G(i) and G(o) signaling. Experimental structures of alpha(2A)AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC(50)) of 52 nanomolar] and two analogs, '7075 and PS75 (EC(50) 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine. Structure-based discovery of nonopioid analgesics acting through the alpha(2A)-adrenergic receptor.,Fink EA, Xu J, Hubner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA, Moroz YS, Huang XP, Kalyanaraman C, Gahbauer S, Chen G, Liu Z, Jacobson MP, Irwin JJ, Bouvier M, Du Y, Shoichet BK, Basbaum AI, Gmeiner P Science. 2022 Sep 30;377(6614):eabn7065. doi: 10.1126/science.abn7065. Epub 2022 , Sep 30. PMID:36173843 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Monoclonal Antibodies 3D structures Transducin 3D structures

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