6S2I

Anti-tumor antibody 14F7-derived scFv in complex with NeuGc Gm3

Summary for 6S2I

• Entry DOI: 10.2210/pdb6s2i/pdb
• Related: 6FFJ
• Descriptor: scFv C1, N-glycolyl-alpha-neuraminic acid-(2-3)-beta-D-galactopyranose-(1-4)-beta-D-glucopyranose (3 entities in total)
• Functional Keywords: ganglioside, complex, scfv, antibody fragment, single chain fragment variable, immuno therapy, 14f7, antitumor protein, gm3
• Biological source: Mus musculus
• Total number of polymer chains: 8
• Total formula weight: 225579.46

Authors

Bjerregaard-Andersen, K.,Heggelund, J.E.,Krengel, U. (deposition date: 2019-06-20, release date: 2020-07-15, Last modification date: 2024-11-06)

Primary citation

Bjerregaard-Andersen, K.,Abraha, F.,Johannesen, H.,Oscarson, S.,Moreno, E.,Krengel, U.
Key role of a structural water molecule for the specificity of 14F7-An antitumor antibody targeting the NeuGc GM3 ganglioside.
Glycobiology, 31:1500-1509, 2021

PubMed Abstract: Tumor-associated glycolipids such as NeuGc GM3 are auspicious molecular targets in antineoplastic therapies and vaccine strategies. 14F7 is a monoclonal IgG1 with high clinical potential in cancer immunotherapy as it displays extraordinary specificity for NeuGc GM3, while it does not recognize the very similar, ubiquitous NeuAc GM3. Here we present the 2.3 Å crystal structure of the 14F7 antigen-binding domain (14F7 scFv) in complex with the NeuGc GM3 trisaccharide. Modeling analysis and previous mutagenesis data suggest that 14F7 may also bind to an alternative NeuGc GM3 conformation, not observed in the crystal structure. The most intriguing finding, however, was that a water molecule centrally placed in the complementarity-determining region directly mediates the specificity of 14F7 to NeuGc GM3. This has profound impact on the complexity of engineering in the binding site and provides an excellent example of the importance in understanding the water structure in antibody-antigen interactions.

PubMed: 34735569
DOI: 10.1093/glycob/cwab076

Experimental method

X-RAY DIFFRACTION (2.285 Å)