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Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers

HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerizatio...

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Detalles Bibliográficos
Autores principales: Zhao, Jun, Mohan, Nishant, Nussinov, Ruth, Ma, Buyong, Wu, Wen Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931022/
https://www.ncbi.nlm.nih.gov/pubmed/33557368
http://dx.doi.org/10.3390/antib10010007
Descripción
Sumario:HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerization of HER2 in HER2-overexpressing breast cancer cells, which attenuates HER2-mediated signaling. Trastuzumab binds to the domain IV of the HER2 extracellular domain and does not directly block the dimerization interface of HER2-HER2 molecules. The three-dimensional structures of the tyrosine kinase domains of ErbB/HER family receptors show asymmetrical packing of the two monomers with distinct conformations. One monomer functions as an activator, whereas the other acts as a receiver. Once activated, the receiver monomer phosphorylates the activator or other proteins. Interestingly, in our previous work, we found that the binding of trastuzumab induced phosphorylation of HER2 with the phosphorylation pattern of HER2 that is different from that mediated by epidermal growth factor (EGF) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Binding of trastuzumab to HER2 promoted an allosteric effect of HER2, in both tyrosine kinase domain and ectodomain of HER2 although details of allosteric regulation were missing. In this study, we utilized molecular dynamics (MD) simulations to model the allosteric consequences of trastuzumab binding to HER2 homodimers and heterodimers, along with the apo forms as controls. We focused on the conformational changes of HER2 in its monomeric and dimeric forms. The data indicated the apparent dual role of trastuzumab as an antagonist and an agonist. The molecular details of the simulation provide an atomic level description and molecular insight into the action of HER2-targeted antibody therapeutics.