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Abstract Details

Eptinezumab:CGRP Complex Structure and Characterization of the Ligand Binding Interface
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To delineate the molecular binding mode of eptinezumab to CGRP by solving the crystal structure of the unbound eptinezumab Fab fragment and its complex with CGRP.
Eptinezumab is a humanized monoclonal antibody that selectively and potently inhibits CGRP, demonstrating rapid engagement of the target ligand and reliable duration of action. 
Eptinezumab Fab fragments—alone and in complex with a-CGRP peptide (hereafter, CGRP)—were purified, concentrated, and screened for crystallization. The tridimensional structure of the complex and the unbound Fab fragment were determined by X-ray diffraction data. Molecular dynamics simulations were performed to analyze the transition between unbound and bound states.
The atomic resolution tridimensional eptinezumab:CGRP complex molecular structure reveals that CGRP binds in a deep, narrow pocket formed by eptinezumab Fab heavy and light chains. There is extensive contact between all 6 complementarity-determining regions of eptinezumab and CGRP. Eleven of 12 CGRP amino acids visible in the crystal structure are in contact with eptinezumab Fab. The complex has high ligand-binding surface area dominated by aromatic residues, likely driving interaction selectivity and specificity. Eptinezumab contains a disulfide bond in L3, which stabilizes this loop, contributes surface area to the binding pocket, and provides van der Waals contacts. Comparison of unbound and complex structures reveals key motion near the binding cleft: heavy chain CDR loops H2 and H3 are displaced by ~1.4–2.0 Å; residue H-Tyr33 changes conformation; and CDR loop H1 is stabilized such that it is visible in the co-structure. These conformational changes create a “latch-and-lock” mechanism for binding CGRP and preventing dissociation.
Unique attributes of the eptinezumab molecular structure Fab region shed light on the specificity, durability, and strength of binding to CGRP. Details of the eptinezumab:CGRP complex structure and comparison to the unbound structure significantly advance our understanding of eptinezumab’s mechanism of action.
Authors/Disclosures

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