The role of intrinsically disordered domains in regulating G protein coupled receptor signaling.

ABSTRACT: The α_2A adrenergic receptor (α_2AAR) is a clinically important target for various diseases including hypertension, diabetes and chronic pain. Here, using single-molecule fluorescence resonance energy transfer imaging, we show how agonist-specific activation dynamics in both structured transmembrane domain (TMD) and intrinsically disorders regions (IDRs) of α_2AAR lead to diverse signaling profiles. Through seven pairs of strategically designed fluorophore labels, we systematically investigate the real-time conformational changes of α_2AAR. Our study reveals unique TM6 dynamics in α_2AAR, featured by a high energy barrier for agonist-induced outward movements essential for activation. In contrast, we identify agonist-specific conformational

SUBMITTER: Xu J 

PROVIDER: S-EPMC12439954 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature