The superfamily of G-protein coupled receptors (GPCRs) is one of the largest gene families in the mammalian genome. GPCRs represent >50% of all current drug targets for treating numerous diseases that affect both peripheral and central nervous systems. Identification of novel GPCR drug targets and their promise for treatment in psychiatric disease has been recently slowed by the dearth of selective targets and changes in the pharmaceutical landscape. However, several recent advances in GPCR crystallization and in vivo pharmacology offer potentially exciting opportunities for therapeutics that target GPCRs in unique ways to treat psychiatric diseases (Kenakin and Christopoulos, 2013).

A recent and elegant development in this field has the potential to greatly advance our understanding of functional selectivity and to open new doors for drug discovery. The study uncovered a ‘snapshot’ of the serotonin 5HT2B receptor bound to ergotamine, an arrestin-biased ligand at this receptor (Wacker et al, 2013). For the first time, this paper and its complementary study, elucidated the molecular signature of the G-protein vs arrestin-biased conformation at serotonin receptors using an X-ray crystallography approach. Together, these reports suggest that for a GPCR to occupy an arrestin-biased (alternate-agonist) state, the ligand-receptor conformation sits in an intermediate state that includes both active and inactivate components, yet also interferes with G-protein signaling.

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