9AXO

Crystal Structure of Antibody HY11-7E1_Ch2 Fab in Complex with Fentanyl

9AXO の概要

• エントリーDOI: 10.2210/pdb9axo/pdb
• 分子名称: HY11-7E1_Ch2 Fab Heavy Chain, HY11-7E1_Ch2 Fab Light Chain, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: opioids, mab, fentanyl, cross-reactive, immune system
• 由来する生物種: Mus musculus; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 50187.68

構造登録者

Rodarte, J.V.,Pancera, M. (登録日: 2024-03-06, 公開日: 2024-10-02, 最終更新日: 2025-03-12)

主引用文献

Rodarte, J.,Baehr, C.,Hicks, D.,McGovern, M.,Zhang, Y.,Silva-Ortiz, P.,Hannon, B.,Duddu, S.,Pancera, M.,Pravetoni, M.
Structure-Based Engineering of Monoclonal Antibodies for Improved Binding to Counteract the Effects of Fentanyl and Carfentanil.
Acs Omega, 9:42506-42519, 2024

PubMed Abstract: The opioid overdose epidemic is a growing and evolving public health crisis fueled by the widespread presence of fentanyl and fentanyl analogues (F/FAs) in both street mixtures and counterfeit pills. To expand current treatment options, drug-targeting monoclonal antibodies (mAbs) offer a viable therapeutic for both pre- and postexposure clinical scenarios. This study reports the isolation, characterization, and efficacy of two murine mAb families targeting fentanyl, carfentanil, or both. Because humanization of the mAbs by CDR grafting negatively impacted affinity for both fentanyl and carfentanil, crystal structures of mAbs in complex with fentanyl or carfentanil were analyzed to identify key residues involved in ligand binding in murine versus humanized structures, and site-directed mutagenesis was used to verify their functional importance. The structural analysis identified a framework residue, Tyr36, present in the murine germline sequence of two mAbs, which was critical for binding to fentanyl and carfentanil. These studies emphasize the importance of structural considerations in mAb engineering to optimize mAbs targeting small molecules including opioids and other drugs of public health interest.

PubMed: 39431098
DOI: 10.1021/acsomega.4c06617

実験手法

X-RAY DIFFRACTION (2.1 Å)