Structural Features for Functional Selectivity at Serotonin Receptors

Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or non-canonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies that show that the hallucinogen lysergic acid diethylamide (LSD), its precursor ergotamine (ERG) and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-hydroxytryptamine (5-HT) receptor 5-HT2B, while being relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG, and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure-function to date, insight into different GPCR signaling pathways are important to better understand both adverse and favorable therapeutic activities.