9FIK

Structure of the FAB fragment of the Antibody NTF30037 in complex with NTF3

Summary for 9FIK

• Entry DOI: 10.2210/pdb9fik/pdb
• Descriptor: Neurotrophin-3, NTF30037 Heavy Chain, NTF30037 Light Chain, ... (7 entities in total)
• Functional Keywords: ntf3, phage display, x ray crystallography, antibody, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 62380.38

Authors

Gallego, P.,Aagaard, A.,Sjogren, T.,Chin, S.,Neal, F. (deposition date: 2024-05-29, release date: 2025-04-02, Last modification date: 2025-04-09)

Primary citation

Chin, S.E.,Gallego, P.,Aagaard, A.,Carmen, S.,Barrett, N.,Wolny, M.,Cloarec, S.,Paterson, J.,Sivapalan, R.,Hunt, J.,Murray, T.V.,Delaney, T.,Sjogren, T.,Neal, F.
Identification of unique binding mode anti-NTF3 antibodies from a novel long VH CDR3 phage display library.
Slas Discov, 31:100216-100216, 2025

PubMed Abstract: Neurotrophic factor 3 (NTF3) is a cysteine knot protein and a member of the nerve growth factor (NGF) family of cytokines. NTF3 engages the Trk family of receptor tyrosine kinases, playing a pivotal role in the development and function of both the central and peripheral nervous systems. Its involvement in neuronal survival, differentiation, and growth links NTF3 to a spectrum of neurodegenerative diseases. Consequently, targeting NTF3 with antibodies holds promise as a first in class therapeutic opportunity for a wide range of conditions. Specific and neutralizing antibodies against NTF3 were successfully isolated using phage display. Initial phage display selections revealed a preference of hits for a longer than average complementarity-determining region 3 (CDR3) in the heavy chain variable domain (VH). To investigate this further we developed a long loop length VH CDR3 antibody library that demonstrated increased hit rates versus a standard antibody library and allowed the isolation of IgG that demonstrated inhibition of functional activity, coupled with a favourable kinetic profile. Structural analysis of the Fab/NTF3 interaction, via X-ray crystallography, unveiled an unconventional interaction wherein regions beyond the longer CDR loops of the Fab induced ordering in a flexible loop on NTF3, which remained disordered in its free antigenic state. This comprehensive approach not only sheds light on the therapeutic potential of NTF3-specific antibodies but also provides critical structural details that enhance our understanding of the complex NTF3-Fab interaction thus offering valuable insights for future antibody design and therapeutic development.

PubMed: 39832740
DOI: 10.1016/j.slasd.2025.100216

Experimental method

X-RAY DIFFRACTION (1.86 Å)