Buckle up! How the nano-seatbelt MRAP1 fastens ACTH in its orthosteric seat

Specific binding of the adrenocorticotropic hormone (ACTH) to the melanocortin-2 receptor (MC2R) requires the presence of the melanocortin-2 receptor accessory protein 1 (MRAP1) to induce stress responses via adrenal synthesis and secretion of glucocorticoids. In a recent study published in Cell Research, Luo et al. determined the cryo-EM structure of the ACTH-bound MC2R in complex with the heterotrimeric G protein Gs and MRAP1, which provides important new insights into the molecular mechanism of accessory protein-dependent regulation of ligand binding and signaling of G protein-coupled receptors.