Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab)

• Main Authors: Fernando Garces, Christopher Mohr, Li Zhang, Ching-Shin Huang, Qing Chen, Chadwick King, Cen Xu, Zhulun Wang
• Format: Article
• Language: English
• Published: Elsevier 2020-02-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720300383

Summary: 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. : Migraine is a neurological condition that affects more than 10% of the world population, and it is related to aberrant CGRPR signaling. Garces et al. describe the molecular mechanism by which erenumab, the first human antibody approved by the FDA for migraine prevention, specifically targets CGRPR pathway, preventing migraine. Keywords: CGRPR, erenumab, migraine, monoclonal antibodies, GPCR, CDR-H3 loop, Aimovig