抗抑郁药
受体
跨膜结构域
兴奋剂
5-羟色胺受体
血清素
生物
化学
神经科学
药理学
生物物理学
生物化学
海马体
作者
Uriel López-Sánchez,Lachlan Munro,Lucy Kate Ladefoged,Anders Juel Pedersen,Christian Colding Brun,Signe Meisner Lyngby,Delphine Baud,Céline Juillan‐Binard,Miriam Grønlund Pedersen,Sarah C. R. Lummis,Benny Bang‐Andersen,Birgit Schiøtt,Christophe Chipot,Guy Schoehn,Jacques Neyton,François Dehez,Hugues Nury,Anders S. Kristensen
标识
DOI:10.1038/s41594-024-01282-x
摘要
Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT3 receptor (5-HT3R), which features two properties: VTX acts differently on rodent and human 5-HT3R, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HT3R and an agonist-bound-like state of human 5-HT3R, in line with the functional profile of the drug. We report four human 5-HT3R structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.
科研通智能强力驱动
Strongly Powered by AbleSci AI