antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility

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 stu...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 105; no. 16; pp. 6109 - 6114
Main Authors Lammerts van Bueren, Jeroen J, Bleeker, Wim K, Brännström, Annika, von Euler, Anne, Jansson, Magnus, Peipp, Matthias, Schneider-Merck, Tanja, Valerius, Thomas, van de Winkel, Jan G.J, Parren, Paul W.H.I
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 22.04.2008
National Acad Sciences
Subjects
Animals
Antibodies
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - pharmacology
Binding Sites
Biochemistry
Biological Sciences
Cell adhesion & migration
Cell division
Cell growth
Cell Line, Tumor
Cell membranes
Crystal structure
Dimerization
Dimers
Epidermal Growth Factor - chemistry
Epidermal Growth Factor - pharmacology
Epitope Mapping
Growth factor receptors
Humans
Immune system
Ligands
Mice
Microscopy, Electron
Molecules
Mutation
Protein Conformation
Proteins
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - genetics
Receptors
Signal Transduction - drug effects
Tomography
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Summary: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.
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Edited by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, and approved February 7, 2008
Author contributions: J.J.L.v.B., W.K.B., J.G.J.v.d.W., and P.W.H.I.P. designed research; J.J.L.v.B., A.B., A.v.E., M.P., and T.S.-M. performed research; J.J.L.v.B., W.K.B., A.B., A.v.E., M.J., T.V., J.G.J.v.d.W., and P.W.H.I.P. analyzed data; and J.J.L.v.B., W.K.B., A.B., J.G.J.v.d.W., and P.W.H.I.P. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0709477105