9AXO

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

Summary for 9AXO

• Entry DOI: 10.2210/pdb9axo/pdb
• Descriptor: HY11-7E1_Ch2 Fab Heavy Chain, HY11-7E1_Ch2 Fab Light Chain, GLYCEROL, ... (5 entities in total)
• Functional Keywords: opioids, mab, fentanyl, cross-reactive, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 2
• Total formula weight: 50187.68

Authors

Rodarte, J.V.,Pancera, M. (deposition date: 2024-03-06, release date: 2024-10-02, Last modification date: 2025-03-12)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)