Insights into ErbB signaling from the structure of the ErbB2–pertuzumab complex

We have determined the 3.2 A ̊ X-ray crystal structure of the extracellular domain of the human epidermal growth factor receptor 2 (ErbB2 or HER2) in a complex with the antigen binding fragment of pertuzumab, an anti-ErbB2 monoclonal antibody also known as 2C4 or Omnitarg. Pertuzumab binds to ErbB2 near the center of domain II, sterically blocking a binding pocket necessary for receptor dimerization and signaling. The ErbB2-pertuzumab structure, combined with earlier mutagenesis data, defines the pertuzumab residues essential for ErbB2 interaction. To analyze the ErbB2 side of the interface, we have mutated a number of residues contacting pertuzumab and examined the effects of these mutations on pertuzumab binding and ErbB2-ErbB3 heterodimerization. We have also shown that conserved residues previously shown to be necessary for EGF receptor homodimerization may be dispensible for ErbB2-ErbB3 heterodimerization. Introduction membrane helix, a tyrosine kinase domain most closely related to the Janus kinases and in the same family as other receptor Epidermal growth factor receptors (also known as ErbBs) and tyrosine kinases (Hanks and Hunter, 1995), and a C-terminal their ligands exist in all higher eukaryotes, including C. elegans tail (the length of which varies between family members) con-(Aroian et al., 1990) and Drosophila (Livneh et al., 1985; Wads- taining a number of tyrosine phosphorylation sites that serv