Revisiting the serotonin binding pose of the 5-HT2A receptor with cryo-EM

The 5-HT2A receptor is a central serotonin GPCR target in drug discovery, implicated in both psychiatric disorders and the pharmacology of psychedelic therapeutics. In this poster, Sygnature Discovery shares structural insights into serotonin’s binding pose at 5-HT2A, obtained via cryo-electron microscopy (cryo-EM) – an approach that reveals novel confirmations missed by traditional crystallography.

Structural Biology Meets Drug Discovery

Cryo-EM has emerged as the preferred technique for elucidating GPCR structures, capturing both agonist-bound active states and, increasingly, antagonist-bound inactive states. However, obtaining these structures – especially inactive-state confirmations- can be challenging due to the size, flexibility and instability of GPCRs in isolation.

This poster shared practical strategies and critical decision points for projects aimed at resolving GPCR complexes using cryo-EM. These insights are particularly relevant for teams pursuing structure-based drug design in the context of CNS pharmacology and GPCR modulation.

A Novel Serotonin Binding Pose

We showcase a newly obtained cryo-EM structure of the 5-HT2A receptor, which reveals a previously unprecedented serotonin binding confirmation. In contrast to earlier X-Ray crystallography models, this structure offers a pose that better reflects serotonin’s expected pharmacological behaviour.

Importantly, the complete receptor complex resolved via cryo-EM proved essential – without it, the previously reported crystallographic data may mislead subsequent ligand design and small molecule optimization efforts.

Supporting GPCR-Targeted CNS Discovery

At Sygnature Discovery, our structural biology team provides expertise in cryo-EM, X-ray crystallography and NMR- working hand-in-hand with pharmacologist and chemists to translate structural insights into drug discovery outcomes.

Contact our experts to discuss your target structure or CNS program.