Balanced or biased G protein and arrestin transmembrane signaling by the adenosine 2A receptor (A_2AAR) is related to ligand-induced allosterically triggered variation of structural dynamics in the intracellular half of the transmembrane domain (TMD). ¹⁹F-nuclear magnetic resonance (NMR) of a network of genetically introduced meta-trifluoromethyl-L-phenylalanine (mtfF) probes in the core of the TMD revealed signaling-related structure rearrangements leading from the extracellular orthosteric drug-binding site to the G protein and arrestin contacts on the intracellular surface. The key element in this structural basis of signal transfer is dynamic loss of structural order in the intracellular half of the TMD, as manifested by local polymorphisms and associated rate processes within the molecular architecture determined previously by X-ray crystallography. This visualization of the structural basis of G protein-coupled receptor (GPCR) activation presents an alternative paradigm for optimizing biased signaling in drug design.