Extra-helical allosteric binding site of apomorphine in ADGRG6

Adhesion G protein-coupled receptors (ADGRs), the second largest G protein-coupled receptor (GPCR) subfamily, orchestrate diverse physiological processes, including development, immune regulation, and nervous system function 1 , 2 . Within this family, ADGRG6 (also termed GPR126) serves as a central regulator of Schwann cell development and peripheral nervous myelination 3 . Dysregulation of ADGRG6 has been implicated in pathological conditions such as scoliosis 4 , 5 , congenital contractures 6 , and breast cancer 7 . Despite the growing physiological and pharmacological relevance of ADGRG6, the structural mechanism underlying ADGRG6 activation, particularly in response to small-molecule ligands, remains elusive. Pharmacological studies have identified apomorphine hydrochloride, a classical dopamine receptor agonist, as a modulator of ADGRG6 that promotes Schwann cell differentiation and myelination through G s -mediated signaling 8 . However, the molecular basis of apomorphine recognition and receptor activation has not been resolved.