Structural basis of psychedelic LSD recognition at dopamine D₁ receptor.

Area of Science:

• Neuroscience
• Pharmacology
• Structural Biology

Background:

• The psychoactive and therapeutic effects of lysergic acid diethylamide (LSD) are linked to its receptor kinetics and signaling.
• While LSD's interaction with serotonin receptors is well-studied, its effects on dopamine receptors remain less understood.

Purpose of the Study:

• To elucidate the binding mode and kinetics of LSD at the dopamine D1 receptor (DRD1).
• To investigate the determinants of G protein versus β-arrestin coupling at DRD1 in the presence of LSD.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structures of LSD/PF6142-bound DRD1-legobody complexes.
• Utilized a β-arrestin-mimicking nanobody (NBA3) to probe coupling mechanisms.
• Kinetic assays to measure ligand dissociation rates.

Main Results:

• Determined cryo-EM structures of LSD bound to DRD1, revealing a unique binding pose with the ergoline moiety near TM4.
• Observed an exceptionally rapid dissociation rate of LSD from DRD1, attributed to the flexibility of extracellular loop 2 (ECL2).
• Demonstrated that G protein binding stabilizes ECL2, significantly slowing the dissociation rate of LSD.

Conclusions:

• LSD exhibits distinct binding and rapid dissociation kinetics at DRD1.
• The flexibility of ECL2 is a key factor in LSD's rapid dissociation from DRD1.
• G protein engagement modulates DRD1 conformation and ligand-receptor interactions, influencing signal transduction pathways relevant to GPCRs.