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.
Franklin
Matthew C
MC
Department of Protein Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94114 USA.
Carey
Kendall D
KD
Vajdos
Felix F
FF
Leahy
Daniel J
DJ
de Vos
Abraham M
AM
Sliwkowski
Mark X
MX
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D001665:Binding Sites; D001666:Binding Sites, Antibody; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; C485206:pertuzumab