8w8b
Cryo-EM structure of SEP-363856 bounded serotonin 1A (5-HT1A) receptor-Gi protein complex
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedTrace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous beta-phenylethylamine (beta-PEA)(1) as well as methamphetamine (METH)(2), an abused substance that has posed a severe threat to human health and society(3). Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction(2,4,5). Here we report structures of human TAAR1-G protein complexes bound to METH and beta-PEA as well as complexes bound to RO5256390, a TAAR1 selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT(1A)R(6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of METH recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like ECL2 helix/loop structure and a hydrogen-bonding network in the ligand binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders. Recognition of methamphetamine and other amines by trace amine receptor TAAR1.,Liu H, Zheng Y, Wang Y, Wang Y, He X, Xu P, Huang S, Yuan Q, Zhang X, Wang L, Jiang K, Chen H, Li Z, Liu W, Wang S, Xu HE, Xu F Nature. 2023 Nov 7. doi: 10.1038/s41586-023-06775-1. PMID:37935377[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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