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TitleStructural insights into the lipid and ligand regulation of serotonin receptors.
Journal, issue, pagesNature, Vol. 592, Issue 7854, Page 469-473, Year 2021
Publish dateMar 24, 2021
AuthorsPeiyu Xu / Sijie Huang / Huibing Zhang / Chunyou Mao / X Edward Zhou / Xi Cheng / Icaro A Simon / Dan-Dan Shen / Hsin-Yung Yen / Carol V Robinson / Kasper Harpsøe / Bo Svensson / Jia Guo / Hualiang Jiang / David E Gloriam / Karsten Melcher / Yi Jiang / Yan Zhang / H Eric Xu /
PubMed AbstractSerotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter that activates the largest subtype family of G-protein-coupled receptors. Drugs that target 5-HT, 5-HT, 5-HT and other 5-HT ...Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter that activates the largest subtype family of G-protein-coupled receptors. Drugs that target 5-HT, 5-HT, 5-HT and other 5-HT receptors are used to treat numerous disorders. 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 in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT bound to 5-HT; and 5-HT in complex with a 5-HT- and 5-HT-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT interface, and is able to increase 5-HT-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT, 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 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.
External linksNature / PubMed:33762731
MethodsEM (single particle)
Resolution2.9 - 3.1 Å
Structure data

EMDB-30971, PDB-7e2x:
Apo serotonin 1A (5-HT1A) receptor-Gi protein complex
Method: EM (single particle) / Resolution: 3 Å

EMDB-30972, PDB-7e2y:
Serotonin-bound Serotonin 1A (5-HT1A) receptor-Gi protein complex
Method: EM (single particle) / Resolution: 3 Å

EMDB-30973, PDB-7e2z:
Aripiprazole-bound serotonin 1A (5-HT1A) receptor-Gi protein complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-30974, PDB-7e32:
Serotonin 1D (5-HT1D) receptor-Gi protein complex
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-30975, PDB-7e33:
Serotonin 1E (5-HT1E) receptor-Gi protein complex
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-J40:
[(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

ChemComp-HOH:
WATER / Water

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM / Serotonin

ChemComp-9SC:
7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one / antipsychotic*YM / Aripiprazole

ChemComp-HVU:
3-(1-methylpiperidin-4-yl)-1H-indol-5-ol / agonist*YM / BRL-54443

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN / Serotonin / 5-HT1A / GPCR / Complex / G protein / Gi / aripiprazole / 5-HT1D / 5-HT1e / BRL-54443

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