Pilot the pulse: controlling the multiplicity of receptor dynamics

• GPCRs are integrative signaling hubs which can change their signaling dynamically in space and time.
• Dynamic ligand binding is a novel basis for the rational design of partial agonists for any GPCR.
• Dualsteric GPCR targeting might generally lead to biased agonism.
• Compartmentalized GPCR signaling is a new principle which may translate into drug discovery.

G protein-coupled receptors (GPCRs) are involved in almost every (patho)physiological process, which explains their importance as drug targets. GPCRs have long been regarded as on/off-switches, which is reflected by direct activation or blockade of these receptors through the majority of marketed GPCR drugs. In recent years, however, our view of GPCRs has changed dramatically. GPCRs are now appreciated as integrative and highly dynamic signaling machines which can adopt numerous distinct conformations enabling them to initiate a highly ramified signaling network. We argue here that it may be possible to chemically encode distinct signaling profiles into ligands by rational ligand design. We exemplify our hypothesis by fine-tuning partial and biased agonism, thereby exploiting two new principles of GPCR modulation – dynamic and dualsteric ligand binding. We propose that the emerging understanding of the multiplicity of receptor dynamics will eventually lead to rationally designed new drugs which pilot the pulse; in other words, that stabilize distinct receptor states to fine-tune GPCR signaling.