8YHZ

The co-crystal structure of the Fab fragment of Ab-1080 with NaV1.7 VSDII peptide

Summary for 8YHZ

• Entry DOI: 10.2210/pdb8yhz/pdb
• Descriptor: Light chain of 1080 Fab, Heavy chain of 1080 Fab, Sodium channel protein type 9 subunit alpha, ... (4 entities in total)
• Functional Keywords: inhibitor, nav1.7, membrane protein/immune system, membrane protein-immune system complex
• Biological source: Oryctolagus cuniculus; More
• Total number of polymer chains: 3
• Total formula weight: 47413.72

Authors

Du, J.,Zhang, Y.,Zhu, R.,Ding, Y. (deposition date: 2024-02-28, release date: 2024-10-23, Last modification date: 2024-12-04)

Primary citation

Zhang, Y.,Ding, Y.,Zeng, Z.,Zhu, R.,Zheng, P.,Fan, S.,Cao, Q.,Chen, H.,Ren, W.,Wu, M.,Wang, L.,Du, J.
Intra-channel bi-epitopic crosslinking unleashes ultrapotent antibodies targeting Na V 1.7 for pain alleviation.
Cell Rep Med, 5:101800-101800, 2024

PubMed Abstract: Crucial for cell activities, ion channels are key drug discovery targets. Although small-molecule and peptide modulators dominate ion channel drug discovery, antibodies are emerging as an alternative modality. However, challenges persist in generating potent antibodies, especially for channels with limited extracellular epitopes. We herein present a bi-epitopic crosslinking strategy to overcome these challenges, focusing on Na1.7, a potential analgesic target. Aiming to crosslink two non-overlapping epitopes on voltage-sensing domains II and IV, we construct bispecific antibodies and ligand-antibody conjugates. Enhanced affinity and potency are observed in comparison to the monospecific controls. Among them, a ligand-antibody conjugate (1080-PEG-ACDTB) displays a two-orders-of-magnitude improvement in potency (IC of 0.06 ± 0.01 nM) and over 1,000-fold selectivity for Na1.7. Additionally, this conjugate demonstrates robust analgesic effects in mouse pain models. Our study introduces an approach to developing effective antibodies against Na1.7, thereby initiating a promising direction for the advancement of pain therapeutics.

PubMed: 39461335
DOI: 10.1016/j.xcrm.2024.101800

Experimental method

X-RAY DIFFRACTION (1.62 Å)