3H3B

Crystal structure of the single-chain Fv (scFv) fragment of an anti-ErbB2 antibody chA21 in complex with residues 1-192 of ErbB2 extracellular domain

Summary for 3H3B

• Entry DOI: 10.2210/pdb3h3b/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-2, anti-ErbB2 antibody chA21 (3 entities in total)
• Functional Keywords: immunoglobulin, beta-helix, protein-protein complex, atp-binding, disulfide bond, kinase, nucleotide-binding, receptor, transferase, transmembrane, tyrosine-protein kinase, 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: 4
• Total formula weight: 98458.05

Authors

Zhou, H.,Liu, Y.,Niu, L.,Zhu, J.,Teng, M. (deposition date: 2009-04-16, release date: 2010-04-28, Last modification date: 2024-10-30)

Primary citation

Zhou, H.,Zha, Z.,Liu, Y.,Zhang, H.,Zhu, J.,Hu, S.,Shen, G.,Cheng, L.,Niu, L.,Greene, M.I.,Teng, M.,Liu, J.
Structural Insights into the Down-regulation of Overexpressed p185her2/neu Protein of Transformed Cells by the Antibody chA21.
J.Biol.Chem., 286:31676-31683, 2011

PubMed Abstract: p185(her2/neu) belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185(her2/neu) monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185(her2/neu) mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185(her2/neu)-overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185(her2/neu), which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185(her2/neu). We propose a structure-based model in which chA21 cross-links two p185(her2/neu) molecules on separate homo- or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process."

PubMed: 21680730
DOI: 10.1074/jbc.M111.235184

Experimental method

X-RAY DIFFRACTION (2.45 Å)