6UMJ

Crystal structure of erenumab Fab-c

6UMJ の概要

• エントリーDOI: 10.2210/pdb6umj/pdb
• 関連するPDBエントリー: 6UMG 6UMH 6UMI
• 分子名称: erenumab Fab heavy chain, IgG1, erenumab Fab light chain, IgG1, 1,3-BUTANEDIOL, ... (5 entities in total)
• 機能のキーワード: fragment antigen binding, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48637.32

構造登録者

Mohr, C. (登録日: 2019-10-09, 公開日: 2020-02-12, 最終更新日: 2024-11-13)

主引用文献

Garces, F.,Mohr, C.,Zhang, L.,Huang, C.S.,Chen, Q.,King, C.,Xu, C.,Wang, Z.
Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy Aimovig (Erenumab).
Cell Rep, 30:1714-, 2020

PubMed Abstract: 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.

PubMed: 32049005
DOI: 10.1016/j.celrep.2020.01.029

実験手法

X-RAY DIFFRACTION (2.7 Å)