Structural basis for inhibition of the epidermal growth factor receptor by cetuximab Journal Article
| Authors: | Li, S.; Schmitz, K. R.; Jeffrey, P. D.; Wiltzius, J. J. W.; Kussie, P.; Ferguson, K. M. |
| Article Title: | Structural basis for inhibition of the epidermal growth factor receptor by cetuximab |
| 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 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. Copyright © 2005 Elsevier Inc. |
| Keywords: | epidermal growth factor; mutation; antineoplastic agents; protein domain; drug inhibition; protein binding; receptor, epidermal growth factor; drug structure; cetuximab; cancer hormone therapy; cancer inhibition; antibodies, monoclonal; recombinant proteins; crystal structure; models, molecular; dimerization; crystallography, x-ray; protein structure, tertiary; binding sites; receptor affinity; antigen binding; structure analysis; protein structure, quaternary; ligand binding; epidermal growth factor receptor antibody; transforming growth factor alpha; epitopes; immunoglobulin f(ab) fragment; binding, competitive; drug conformation; antigen-antibody complex; immunoglobulin fab fragments; receptor intrinsic activity; receptor aggregation |
| Journal Title: | Cancer Cell |
| Volume: | 7 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2005-04-01 |
| Start Page: | 301 |
| End Page: | 311 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2005.03.003 |
| PUBMED: | 15837620 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 281" - "Export Date: 24 October 2012" - "CODEN: CCAEC" - "Source: Scopus" |
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