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Structure paper

TitleStructural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A.
Journal, issue, pagesSci Adv, Vol. 11, Issue 31, Page eadu9851, Year 2025
Publish dateAug 1, 2025
AuthorsAudrey L Warren / Gregory Zilberg / Anwar Abbassi / Alejandro Abraham / Shifan Yang / Daniel Wacker /
PubMed AbstractActivation of the serotonin receptor 5-HT1A has been shown to regulate mood and cognition, making 5-HT1A an important target in the treatment of anxiety, depression, and psychosis. Although the ...Activation of the serotonin receptor 5-HT1A has been shown to regulate mood and cognition, making 5-HT1A an important target in the treatment of anxiety, depression, and psychosis. Although the receptor signals through inhibitory G proteins, more work is necessary to understand differences in transducer coupling and its relation to functional activity. To develop a molecular understanding of the differences underlying transducer coupling and activation, we performed structure-activity relationship studies of 5-HT1A with distinct G proteins. Through a combination of in vitro assays, we identified a potent partial agonist that selectively engages a G protein subtype. We further investigated the differences in G protein engagement at 5-HT1A with cryo-electron microscopy, determining structures of 5-HT1A bound to distinct ligands and G protein subtypes. Combined with subsequent structure-guided mutagenesis and signaling assays, our studies uncover both orthosteric and allosteric determinants of agonist-specific stimulation of distinct transducers.
External linksSci Adv / PubMed:40749070
MethodsEM (single particle)
Resolution2.74 - 3.03 Å
Structure data

47300

9dyd

EMDB-47300, PDB-9dyd:
Asenapine-bound serotonin 1A (5-HT1A) receptor-Goa protein complex
Method: EM (single particle) / Resolution: 2.96 Å

47301

9dye

EMDB-47301, PDB-9dye:
Buspirone-bound serotonin 1A (5-HT1A) receptor-Goa protein complex
Method: EM (single particle) / Resolution: 2.9 Å

47302

9dyf

EMDB-47302, PDB-9dyf:
Asenapine-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.74 Å

48164

9md1

EMDB-48164, PDB-9md1:
Buspirone-bound serotonin 1A (5-HT1A) receptor-Gz protein complex
Method: EM (single particle) / Resolution: 3.03 Å

Chemicals

PDB-1bir:
RIBONUCLEASE T1, PHE 100 TO ALA MUTANT COMPLEXED WITH 2' GMP

ChemComp-CLR:
CHOLESTEROL

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, No image

ChemComp-YLX:
Unknown entry

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsSIGNALING PROTEIN / GPCR Signaling Complex / Serotonin Receptor

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