3WSQ

Structure of HER2 with an Fab

Summary for 3WSQ

• Entry DOI: 10.2210/pdb3wsq/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Antibody Light Chain, Antibody Heavy Chain (3 entities in total)
• Functional Keywords: kinase, transferase-immune system complex, transferase/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Cytoplasm. Isoform 3: Cytoplasm: P04626
• Total number of polymer chains: 3
• Total formula weight: 107840.00

Authors

Fu, W.Y.,Wang, Y.X.,Zhou, L.J. (deposition date: 2014-03-20, release date: 2015-03-25, Last modification date: 2024-11-13)

Primary citation

Fu, W.,Wang, Y.,Zhang, Y.,Xiong, L.,Takeda, H.,Ding, L.,Xu, Q.,He, L.,Tan, W.,Bethune, A.N.,Zhou, L.
Insights into HER2 signaling from step-by-step optimization of anti-HER2 antibodies.
MAbs, 6:978-990, 2014

PubMed Abstract: HER2, a ligand-free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti-HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer; however, resistance to trastuzumab is common. The development of monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of ErbB2 signaling, especially HER2/HER3 signaling. Use of such antibodies may have clinical benefits if these antibodies can become widely accepted. Here, we describe a novel anti-HER2 antibody, hHERmAb-F0178C1, which was isolated from a screen of a phage display library. A step-by-step optimization method was employed to maximize the inhibitory effect of this anti-HER2 antibody. Crystallographic analysis was used to determine the three-dimensional structure to 3.5 Å resolution, confirming that the epitope of this antibody is in domain III of HER2. Moreover, this novel anti-HER2 antibody exhibits superior efficacy in blocking HER2/HER3 heterodimerization and signaling, and its use in combination with pertuzumab has a synergistic effect. Characterization of this antibody revealed the important role of a ligand binding site within domain III of HER2. The results of this study clearly indicate the unique potential of hHERmAb-F0178C1, and its complementary inhibition effect on HER2/HER3 signaling warrants its consideration as a promising clinical treatment.

PubMed: 24838231
DOI: 10.4161/mabs.28786

Experimental method

X-RAY DIFFRACTION (3.5 Å)