4UV7
The complex structure of extracellular domain of EGFR and GC1118A
Summary for 4UV7
| Entry DOI | 10.2210/pdb4uv7/pdb |
| Descriptor | EPIDERMAL GROWTH FACTOR RECEPTOR, GC1118A, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total) |
| Functional Keywords | transferase, receptor tyrosine kinase, antibody |
| Biological source | HOMO SAPIENS (HUMAN) More |
| Total number of polymer chains | 3 |
| Total formula weight | 118519.41 |
| Authors | |
| Primary citation | Lim, Y.,Yoo, J.,Kim, M.S.,Hur, M.,Lee, E.H.,Hur, H.S.,Lee, J.C.,Lee, S.N.,Park, T.W.,Lee, K.,Chang, K.H.,Kim, K.,Kang, Y.,Hong, K.W.,Kim, S.H.,Kim, Y.G.,Yoon, Y.,Nam, D.H.,Yang, H.,Kim, D.G.,Cho, H.S.,Won, J. Gc1118, an Anti-Egfr Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity Against High-Affinity Egfr Ligands. Mol.Cancer Ther., 15:251-, 2016 Cited by PubMed Abstract: The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. ©2015 AACR. PubMed: 26586721DOI: 10.1158/1535-7163.MCT-15-0679 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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