Key role of a structural water molecule for the specificity of 14F7—An antitumor antibody targeting the NeuGc GM3 ganglioside
| Autor: | Ernesto Moreno, Kaare Bjerregaard-Andersen, Fana Abraha, Stefan Oscarson, Ute Krengel, Hedda Johannesen |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular endocrine system AcademicSubjects/SCI01000 medicine.medical_treatment carbohydrate-antibody interactions Mutagenesis (molecular biology technique) Antineoplastic Agents protein–carbohydrate interactions Biochemistry Structural water Antigen-Antibody Reactions 03 medical and health sciences 0302 clinical medicine Glycolipid Cancer immunotherapy Antibody Specificity medicine G(M3) Ganglioside Protein–carbohydrate interactions Molecule Binding site 030304 developmental biology 0303 health sciences Molecular Structure Chemistry Glycan Recognition Antibodies Monoclonal Water X-ray crystal structure water-mediated antibody specificity 3. Good health carbohydrates (lipids) water-mediated interaction 030220 oncology & carcinogenesis Monoclonal lipids (amino acids peptides and proteins) N-glycolyl GM3 |
| Zdroj: | Glycobiology |
| ISSN: | 1460-2423 0959-6658 |
| DOI: | 10.1093/glycob/cwab076 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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