TY - JOUR
T1 - Structural model of the mAb 806-EGFR complex using computational docking followed by computational and experimental mutagenesis
AU - Sivasubramanian, Arvind
AU - Chao, Ginger
AU - Pressler, Heather M.
AU - Wittrup, K. Dane
AU - Gray, Jeffrey J.
N1 - Funding Information:
A.S. acknowledges support from the Chemical Therapeutics Working Group at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. This work was funded by National Institutes of Health (NIH) R01-CA96504 for K.D.W. and NIH K01-HG02316 for J.J.G. G.C. is the recipient of a National Defense Science and Engineering Graduate Fellowship. mAb 806 was generously provided by Achim Jungbluth of the Ludwig Institute for Cancer Research. J.J.G. and A.S. acknowledge Greg Chirikjian and Jay Jeong for assistance with the Elastic Network Interpolation method for analyzing the pathway of the EGFR conformational change. Thanks to Dan Leahy and Greg Bowman for discussion and review of our manuscript.
PY - 2006/3
Y1 - 2006/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2005.11.022
DO - 10.1016/j.str.2005.11.022
M3 - Article
C2 - 16531225
AN - SCOPUS:33644839662
SN - 0969-2126
VL - 14
SP - 401
EP - 414
JO - Structure
JF - Structure
IS - 3
ER -