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Molecular insights into the modulation of the 5HT 2A receptor by serotonin, psilocin, and the G protein subunit Gqα

Summary

This study uses computer simulations to understand how psilocin (the active compound in magic mushrooms) and serotonin interact with a brain receptor called 5HT 2A R. The research shows that both molecules prefer to bind to a deeper part of the receptor rather than a shallower area, and that a protein called Gqα is essential for keeping the receptor in its active state. These findings could help scientists develop better medicines for depression and anxiety.

Background

The 5HT 2A receptor (5HT 2A R) is a G-protein-coupled receptor that drives neuronal functions and is a target for psychedelic drugs. Understanding ligand interactions and conformational transitions of this receptor is essential for developing effective pharmaceuticals, but mechanistic details of 5HT 2A R activation remain poorly understood.

Objective

This study aimed to investigate 5HT 2A R’s conformational dynamics upon binding to serotonin and psilocin, and to understand the role of G-protein (Gqα) coupling in receptor activation using molecular dynamics simulations and free-energy calculations.

Results

Both serotonin and psilocin exhibit higher binding affinities for the orthosteric binding pocket (OBP) over the extended binding pocket (EBP), with approximately 5 kcal/mol difference. The study discovered an intermediate ‘partially-open’ receptor conformation that occurs in ~55% of simulations. The active ‘open’ state of 5HT 2A R collapses to a closed state in the absence of Gqα, demonstrating the critical importance of G-protein coupling for maintaining receptor activation.

Conclusion

These findings enhance understanding of 5HT 2A R activation mechanisms, revealing intermediate conformational states and ligand binding preferences. The results underscore the essential role of G-protein coupling in stabilizing the active receptor state and may inform the development of novel therapeutics for neurological and psychiatric disorders.
  • Published in:FEBS Letters,
  • Study Type:Computational Study,
  • Source: PMID: 39865564, DOI: 10.1002/1873-3468.15099
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