A Receptor on Acid

Abstract

Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT_2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.

Figure 1. LSD interacts with a unique lid element of the 5-HT receptor to send the brain on an extended bicycle trip

LSD, schematized as a bicycle, exerts its potent psychedelic effects by directly binding to the extracellular surfaces of transmembrane receptors in the brain such as the 5-HT2A and 5-HT2B serotonin receptors. By stabilizing them in conformations that preferentially favor the binding of arrestin (green lobes) at its intracellular surface, LSD induces a mental ‘trip’ from reality. A key feature of LSD required for this effect is its diethylamine substituent (handlebars of the bicycle). One extracellular loop of the receptor serves as a ‘lid’, blocking the exit for LSD, thus making the trip long lasting. This figure is created with the help from Stephanie King (University of Michigan Life Sciences Institute). The LSD bicycle graphic is adapted from the website http://bicycleday.la.