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

Matthew C. Franklin, Kendall D. Carey, Felix F. Vajdos, Daniel J. Leahy, Abraham M. De Vos, Mark X. Sliwkowski

Research output: Contribution to journalArticlepeer-review

Abstract

We have determined the 3.2 Å 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.

Original languageEnglish (US)
Pages (from-to)317-328
Number of pages12
JournalCancer cell
Volume5
Issue number4
DOIs
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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