7e2x
Apo 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 PubMedSerotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter(1,2) that activates the largest subtype family of G-protein-coupled receptors(3). Drugs that target 5-HT(1A), 5-HT(1D), 5-HT(1E) and other 5-HT receptors are used to treat numerous disorders(4). 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT(1A) in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT(1D) bound to 5-HT; and 5-HT(1E) in complex with a 5-HT(1E)- and 5-HT(1F)-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT(1A) interface, and is able to increase 5-HT(1A)-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT(1A), in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT(1A) are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors. Structural insights into the lipid and ligand regulation of serotonin receptors.,Xu P, Huang S, Zhang H, Mao C, Zhou XE, Cheng X, Simon IA, Shen DD, Yen HY, Robinson CV, Harpsoe K, Svensson B, Guo J, Jiang H, Gloriam DE, Melcher K, Jiang Y, Zhang Y, Xu HE Nature. 2021 Apr;592(7854):469-473. doi: 10.1038/s41586-021-03376-8. Epub 2021 , Mar 24. PMID:33762731[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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