Retraction for Lammerts van Bueren et al., The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility
| Autor: | van de Winkel Jg, Lammerts van Bueren Jj, Thomas Valerius, Brännström A, Paul W. H. I. Parren, Wim K. Bleeker, Magnus Jansson, Tanja Schneider-Merck, Matthias Peipp |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Flexibility (anatomy)
Protein Conformation Antibodies Monoclonal Humanized Ligands Zalutumumab Mice Cell Line Tumor medicine Animals Humans Epidermal growth factor receptor Binding Sites Multidisciplinary Epidermal Growth Factor biology Chemistry Intermolecular force Antibodies Monoclonal Limiting Retraction Cell biology ErbB Receptors Microscopy Electron medicine.anatomical_structure Mutation biology.protein Antibody Epitope Mapping Signal Transduction medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 109:5548-5548 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1203736109 |
| Popis: | The epidermal growth factor receptor (EGFR) activates cellular pathways controlling cell proliferation, differentiation, migration, and survival. It thus represents a valid therapeutic target for treating solid cancers. Here, we used an electron microscopy-based technique (Protein Tomography) to study the structural rearrangement accompanying activation and inhibition of native, individual, EGFR molecules. Reconstructed tomograms (3D density maps) showed a level of detail that allowed individual domains to be discerned. Monomeric, resting EGFR ectodomains demonstrated large flexibility, and a number of distinct conformations were observed. In contrast, ligand-activated EGFR complexes were detected only as receptor dimers with ring-like conformations. Zalutumumab, a therapeutic inhibitory EGFR antibody directed against domain III, locked EGFR molecules into a very compact, inactive conformation. Biochemical analyses showed bivalent binding of zalutumumab to provide potent inhibition of EGFR signaling. The structure of EGFR-zalutumumab complexes on the cell surface visualized by Protein Tomography indicates that the cross-linking spatially separates the EGFR molecules' intracellular kinase domains to an extent that appears incompatible with the induction of signaling. These insights into the mechanisms of action of receptor inhibition may also apply to other cell-surface tyrosine kinase receptors of the ErbB family. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|