9DYF

Asenapine-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex

This is a non-PDB format compatible entry.

Summary for 9DYF

• Entry DOI: 10.2210/pdb9dyf/pdb
• EMDB information: 47302
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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: gpcr signaling complex, serotonin receptor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 151369.83

Authors

Warren, A.L.,Zilberg, G.,Wacker, D. (deposition date: 2024-10-14, release date: 2025-08-13)

Primary citation

Warren, A.L.,Zilberg, G.,Abbassi, A.,Abraham, A.,Yang, S.,Wacker, D.
Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A.
Sci Adv, 11:eadu9851-eadu9851, 2025

PubMed Abstract: 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.

PubMed: 40749070
DOI: 10.1126/sciadv.adu9851

Experimental method

ELECTRON MICROSCOPY (2.74 Å)