Structural basis for inhibition of the epidermal growth factor receptor by cetuximab

Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 Å resolution X...

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Bibliographic Details
Published in:Cancer cell 2005-04, Vol.7 (4), p.301-311
Main Authors: Li, Shiqing, Schmitz, Karl R., Jeffrey, Philip D., Wiltzius, Jed J.W., Kussie, Paul, Ferguson, Kathryn M.
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal, Humanized
Antigen-Antibody Complex - chemistry
Antineoplastic Agents - chemistry
Antineoplastic Agents - immunology
Binding Sites - genetics
Binding, Competitive
Cetuximab
Crystallography, X-Ray
Epidermal Growth Factor - chemistry
Epitopes - chemistry
Epitopes - genetics
Humans
Immunoglobulin Fab Fragments - chemistry
Immunoglobulin Fab Fragments - immunology
Immunoglobulin Fab Fragments - pharmacology
Models, Molecular
Mutation - genetics
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary - drug effects
Receptor Aggregation - drug effects
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - chemistry
Receptor, Epidermal Growth Factor - immunology
Recombinant Proteins - chemistry
Recombinant Proteins - immunology
Transforming Growth Factor alpha - chemistry
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Summary:Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 Å resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic “autoinhibited” or “tethered” inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.03.003