7sqo | pdb_00007sqo

Structure of the orexin-2 receptor(OX2R) bound to TAK-925, Gi and scFv16

spinqualitylabelsall models 7sqo, resolution 3.17Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7sqo is a 5 chain structure with sequence from Bos taurus, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.17Å Ligands: A6F, OLA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBG2_BOVIN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. Publication Abstract from PubMed The OX(2) orexin receptor (OX(2)R) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OX(2)R is a proven therapeutic strategy for insomnia drugs, and agonism of OX(2)R is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OX(2)R had been considered 'undruggable.' We harness cryo-electron microscopy of OX(2)R-G protein complexes to determine how the first clinically tested OX(2)R agonist TAK-925 can activate OX(2)R in a highly selective manner. Two structures of TAK-925-bound OX(2)R with either a G(q) mimetic or G(i) reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX(1) and OX(2) receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OX(2)R's coupling selectivity for G(q) signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OX(2)R agonists for narcolepsy and other circadian disorders. Molecular mechanism of the wake-promoting agent TAK-925.,Yin J, Kang Y, McGrath AP, Chapman K, Sjodt M, Kimura E, Okabe A, Koike T, Miyanohana Y, Shimizu Y, Rallabandi R, Lian P, Bai X, Flinspach M, De Brabander JK, Rosenbaum DM Nat Commun. 2022 May 25;13(1):2902. doi: 10.1038/s41467-022-30601-3. PMID:35614071 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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