PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome

Roth and colleagues have developed PRESTO-Tango, a new open-source platform for high-throughput screening of the entire human nonolfactory GPCRome, and they show how it can be used to identify new ligands for orphan human GPCRs. G protein–coupled receptors (GPCRs) are essential mediators of cellular signaling and are important targets of drug action. Of the approximately 350 nonolfactory human GPCRs, more than 100 are still considered to be 'orphans' because their endogenous ligands remain unknown. Here, we describe a unique open-source resource that allows interrogation of the druggable human GPCRome via a G protein–independent β-arrestin–recruitment assay. We validate this unique platform at more than 120 nonorphan human GPCR targets, demonstrate its utility for discovering new ligands for orphan human GPCRs and describe a method (parallel receptorome expression and screening via transcriptional output, with transcriptional activation following arrestin translocation (PRESTO-Tango)) for the simultaneous and parallel interrogation of the entire human nonolfactory GPCRome.