8PKM

Befiradol-bound serotonin 5-HT1A receptor - Gi Protein Complex

Summary for 8PKM

• Entry DOI: 10.2210/pdb8pkm/pdb
• Related: 8PJK
• EMDB information: 17712 17747
• 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: membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 140250.71

Authors

Schneider, J.,Gmeiner, P.,Hove, T.T.,Rasmussen, T.,Boettcher, B. (deposition date: 2023-06-27, release date: 2024-05-29, Last modification date: 2025-07-02)

Primary citation

Ullrich, A.,Schneider, J.,Braz, J.M.,Neu, E.,Staffen, N.,Stanek, M.,Blahova, J.,Hove, T.,Albert, T.,Allikalt, A.,Lober, S.,Bhardwaj, K.,Rodriguez-Rosado, S.,Fink, E.,Rasmussen, T.,Hubner, H.,Inoue, A.,Shoichet, B.K.,Basbaum, A.I.,Bottcher, B.,Weikert, D.,Gmeiner, P.
Discovery of a functionally selective serotonin receptor (5-HT 1A R) agonist for the treatment of pain.
Sci Adv, 11:eadv9267-eadv9267, 2025

PubMed Abstract: The heterotrimeric G protein-coupled serotonin receptor 5-HT receptor (5-HTR) mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, we evolved ST171, a bitopic 5-HTR agonist that revealed highly potent and functionally selective G signaling without G activation and marginal β-arrestin recruitment. ST171 is effective in acute and chronic pain models. Cryo-electron microscopy structures of ST171 bound to 5-HTR in complex with the G protein compared to the canonical agonist befiradol bound to complexes of 5-HTR with G or G revealed that the ligands occupy different exo-sites. The individual binding poses are associated with ligand-specific receptor conformations that were further studied by molecular dynamics simulations, allowing us to better understand ligand bias, a phenomenon that may be crucial to the discovery of more effective and safe G protein-coupled receptor drugs.

PubMed: 40531992
DOI: 10.1126/sciadv.adv9267

Experimental method

ELECTRON MICROSCOPY (2.9 Å)