The 5-HT3 receptor (5-HT3R) is a member of the Cys-loop family of ligand-gated ion channels, which are in both the peripheral and central nervous systems. 5-HT3R is involved in regulation of neurotransmitter systems implicated in the pathophysiology of major depression. In this work, AlphaMol collaborated with Max Planck Institute, discovered that different from traditional homopentamer, 5-TH3R could form different states. This provides a new insight into 5-TH3R drug discovery.
On September 3, 2024, the team of AlphaMol, in collaboration with the Max Planck Institute in Germany, published a research article titled "Structure of Tetrameric Forms of the Serotonin-gated 5-HT3A Receptor Ion Channel" as the cover story in The EMBO Journal.
The serotonin ion channel 5-HT3A receptor (5-HT3AR) is an important drug target, closely related to diseases such as depression, vomiting in cancer patients undergoing radiotherapy and chemotherapy, and pains. The cryo-electron microscopy structure of the 5-HT3AR in a native cellular membrane physiological environment was resolved in this work. Surprisingly, in addition to the traditional pentameric structure, the target was also found to form a tetrameric structure. What's more, this tetrameric structure presents in two different states as "symmetric tetramer" and "asymmetric tetramer".
The team elucidated the molecular mechanism of the receptor's assembly from monomers to multimers in a physiological environment through computer simulation systems. Computer simulations and biochemical experiments showed that the pore space formed by a single 5-HT3AR tetramer is too narrow to accommodate the passage of ions through the channel to perform its physiological roles of signal transduction. The computer simulations also found that the formation of a pentamer from a monomer combined with a tetramer is energetically more favorable than the formation of a pentamer from a dimer combined with a trimer.
This research paper provides new insights and theoretical guidance for understanding the physiological function of 5-HT3AR and designing 5-HT3AR antagonistic drugs.