Structural adaptation associated with signaling preference at the human GHRHR

The growth hormone-releasing hormone receptor (GHRHR), a class B1 G protein-coupled receptor, is essential for somatic growth, metabolism, and tissue repair. Dysregulation of its signal transduction is directly linked to growth disorders and certain cancers, making it a pivotal therapeutic target. To elucidate the structural basis for its conformational plasticity and ligand-dependent signaling, we determined cryo-electron microscopy structures of the human GHRHR in multiple functional states. The ligand-free G_s-coupled (<i>Apo</i>) receptor, while adopting an active-like intracellular conformation, exhibits pronounced extracellular plasticity, characterized by a distinctive outward displacement of the extracellular loop 1 (ECL1). In contrast, the synthetic agonist PCO371 binds to a well-defined allosteric pocket nestled between transmembrane helices in the intracellular half of the receptor, stabilizing the active G_s-coupled complex. Complementary molecular dynamics simulations reveal that the antagonist MIA-602 enforces a rigid, inactive state by locking the conserved HETY motif and preventing the characteristic outward movement of transmembrane helix 6. Together, our integrative structural analysis delineates ligand-specific conformational adaptation, from an open extracellular vestibule in the <i>Apo</i> state, through an intracellular allosteric site, to the restriction of activation motifs, that collectively governs signaling bias and functional selectivity at GHRHR.