The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility
Open Access
- 22 April 2008
- journal article
- retracted article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 105 (16), 6109-6114
- https://doi.org/10.1073/pnas.0709477105
Abstract
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.This publication has 34 references indexed in Scilit:
- An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor ReceptorCell, 2006
- Structural basis for inhibition of the epidermal growth factor receptor by cetuximabCancer Cell, 2005
- Fine Epitope Mapping of anti-Epidermal Growth Factor Receptor Antibodies Through Random Mutagenesis and Yeast Surface DisplayJournal of Molecular Biology, 2004
- EGF Activates Its Receptor by Removing Interactions that Autoinhibit Ectodomain DimerizationMolecular Cell, 2003
- Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular DomainsCell, 2002
- Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor αCell, 2002
- Crystallographic structure of an intact IgG1 monoclonal antibodyJournal of Molecular Biology, 1998
- Maximum-Entropy Three-Dimensional Reconstruction with Deconvolution of the Contrast Transfer Function: A Test Application with AdenovirusJournal of Structural Biology, 1996
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- A TECHNIQUE FOR ULTRACRYOTOMY OF CELL SUSPENSIONS AND TISSUESThe Journal of cell biology, 1973