Calcitonin-gene-related peptide (CGRP) plays a key role in migraine 
pathophysiology. Aimovig (erenumab; erenumab-aooe in the United States) is the 
only US Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) 
therapy against the CGRP receptor (CGRPR) for the prevention of migraine. 
Aimovig is also the first FDA-approved mAb against a G-protein-coupled receptor 
(GPCR). Here, we report the architecture and functional attributes of erenumab 
critical for its potent antagonism against CGRPR. The crystal structure of 
erenumab in complex with CGRPR reveals a direct ligand-blocking mechanism, 
enabled by a remarkable 21-residue-long complementary determining region 
(CDR)-H3 loop, which adopts a tyrosine-rich helix-turn tip and projects into the 
deep interface of the calcitonin receptor-like receptor (CLR) and RAMP1 subunits 
of CGRPR. Furthermore, erenumab engages with residues specific to CLR and RAMP1, 
providing the molecular basis for its exquisite selectivity. Such structural 
insights reveal the drug action mechanism of erenumab and shed light on 
developing antibody therapeutics targeting GPCRs.