Ullrich Annika, Schneider Johannes, Braz João M, Neu Eduard, Staffen Nico, Stanek Markus, Bláhová Jana, Hove Tamsanqa, Albert Tamara, Allikalt Anni, Löber Stefan, Bhardwaj Karnika, Rodriguez-Rosado Sian, Fink Elissa, Rasmussen Tim, Hübner Harald, Inoue Asuka, Shoichet Brian K, Basbaum Allan I, Böttcher Bettina, Weikert Dorothee, Gmeiner Peter
Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Anatomy, University of California, San Francisco, CA, USA.
Sci Adv. 2025 Jun 20;11(25):eadv9267. doi: 10.1126/sciadv.adv9267. Epub 2025 Jun 18.
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.
异源三聚体G蛋白偶联5-羟色胺受体（5-HT受体，5-HTR）介导抗伤害感受，可能是治疗疼痛的一个有价值的靶点。我们从一个化学文库出发，研发出了ST171，一种双位点5-HTR激动剂，它显示出高效且功能选择性的G信号传导，而不激活G蛋白且几乎不招募β-抑制蛋白。ST171在急性和慢性疼痛模型中均有效。与结合5-HTR与G或G蛋白复合物的典型激动剂贝非拉朵相比，ST171与结合G蛋白的5-HTR复合物的冷冻电镜结构表明，这些配体占据不同的外位点。通过分子动力学模拟进一步研究了与配体特异性受体构象相关的各个结合姿势，这使我们能够更好地理解配体偏向性，这一现象对于发现更有效和安全的G蛋白偶联受体药物可能至关重要。
