1YY9

Structure of the extracellular domain of the epidermal growth factor receptor in complex with the Fab fragment of cetuximab/Erbitux/IMC-C225

Summary for 1YY9

• Entry DOI: 10.2210/pdb1yy9/pdb
• Related: 1YY8
• Descriptor: Epidermal Growth Factor Receptor, Cetuximab Fab Light chain, Cetuximab Fab Heavy chain, ... (7 entities in total)
• Functional Keywords: cell surface receptor; tyrosine kinase; glycoprotein; antigen:antibody complex; fab fragment; antitumor; drug, immune system-transferase complex, immune system/transferase
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 3
• Total formula weight: 120235.81

Authors

Li, S.,Schmitz, K.R.,Jeffrey, P.D.,Wiltzius, J.J.W.,Kussie, P.,Ferguson, K.M. (deposition date: 2005-02-24, release date: 2005-04-26, Last modification date: 2024-11-13)

Primary citation

Li, S.,Schmitz, K.R.,Jeffrey, P.D.,Wiltzius, J.J.W.,Kussie, P.,Ferguson, K.M.
Structural basis for inhibition of the epidermal growth factor receptor by cetuximab
Cancer Cell, 7:301-311, 2005

PubMed Abstract: 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 angstroms 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.

PubMed: 15837620
DOI: 10.1016/j.ccr.2005.03.003

Experimental method

X-RAY DIFFRACTION (2.605 Å)