7SR8
Molecular mechanism of the the wake-promoting agent TAK-925
Summary for 7SR8
| Entry DOI | 10.2210/pdb7sr8/pdb |
| Related | 7SQO |
| EMDB information | 25389 25399 |
| Descriptor | a modified Guanine nucleotide-binding protein G(q) subunit alpha, 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, ... (7 entities in total) |
| Functional Keywords | orexin, gpcr, narcolepsy, signaling protein |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 5 |
| Total formula weight | 150380.19 |
| Authors | Yin, J.,Chapman, K.,Lian, P.,De Brabander, J.K.,Rosenbaum, D.M. (deposition date: 2021-11-08, release date: 2022-06-08, Last modification date: 2024-11-13) |
| Primary citation | Yin, J.,Kang, Y.,McGrath, A.P.,Chapman, K.,Sjodt, M.,Kimura, E.,Okabe, A.,Koike, T.,Miyanohana, Y.,Shimizu, Y.,Rallabandi, R.,Lian, P.,Bai, X.,Flinspach, M.,De Brabander, J.K.,Rosenbaum, D.M. Molecular mechanism of the wake-promoting agent TAK-925. Nat Commun, 13:2902-2902, 2022 Cited by PubMed Abstract: The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G 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 and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders. PubMed: 35614071DOI: 10.1038/s41467-022-30601-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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