Structural model of the mAb 806-EGFR complex using computational docking followed by computational and experimental mutagenesis.
In this work, we combined computational protein-protein docking with computational and experimental mutagenesis to predict the structure of the complex formed by monoclonal antibody 806 (mAb 806) and the epidermal growth factor receptor (EGFR). We docked mAb 806, an antitumor antibody, to its epitope of EGFR residues 287-302. Potential mAb 806-EGFR orientations were generated, and computational mutagenesis was used to filter them according to their agreement with experimental mutagenesis data. Further computational mutagenesis suggested additional mutations, which were tested to arrive at a final structure that was most consistent with experimental mutagenesis data. We propose that this is the EGFR-mAb 806 structure, in which mAb 806 binds to an untethered form of the receptor, consistent with published experimental results. The steric hindrance created by the antibody near the EGFR dimer interface interferes with receptor dimerization, and we postulate this as the structural origin for the antitumor effect of mAb 806.
Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, USA.
Arvind
A
Sivasubramanian
Ginger
G
Chao
Heather M
HM
Pressler
K Dane
KD
Wittrup
Jeffrey J
JJ
Gray
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics; D000912:Antibodies, Neoplasm / Q000737:chemistry*; D019295:Computational Biology; D018604:Epitope Mapping; D066246:ErbB Receptors / Q000737:chemistry* / Q000276:immunology*; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis; D011485:Protein Binding; D015203:Reproducibility of Results
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D066246:ErbB Receptors