Dynamic Monomer-Dimer Transition in Ligand-induced Apelin Receptor Activation

G-protein-coupled receptors (GPCRs) are significant signal transducers that exist as monomers and in multiple oligomeric forms. However, molecular mechanism driving their dynamic interconversion to regulate intricate signaling in class A GPCRs remains elusive, compounding our understanding of their related pathophysiological functions. Here, we present a set of 12 assemblies of the apelin receptor (APLNR), including dimeric apo state, monomeric and dimeric intermediate states and fully active state stimulated by small molecule or nanobody, providing a detailed dynamic view of the monomer-dimer transition. High-resolution cryo-EM structures reveal that different ligands induce varying degrees of pre-dissociation in intermediate-state dimers, with G-protein coupling facilitating the transition from dimeric to monomeric receptor. Functional studies further highlight the critical role of cholesterol clusters in stabilizing the APLNR dimers. These insights enhance our understanding of the dynamic regulation of class A GPCRs across different aggregated forms and advance the rational drug design strategies aimed at selectively modulating of APLNR signaling.