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 journalArticle

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

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Dimerization
pertuzumab
Epidermal Growth Factor Receptor
Mutagenesis
Monoclonal Antibodies
X-Rays
Antigens
Mutation
human ERBB2 protein

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Franklin, M. C., Carey, K. D., Vajdos, F. F., Leahy, D. J., De Vos, A. M., & Sliwkowski, M. X. (2004). Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell, 5(4), 317-328. https://doi.org/10.1016/S1535-6108(04)00083-2

Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. / Franklin, Matthew C.; Carey, Kendall D.; Vajdos, Felix F.; Leahy, Daniel J.; De Vos, Abraham M.; Sliwkowski, Mark X.

In: Cancer Cell, Vol. 5, No. 4, 04.2004, p. 317-328.

Research output: Contribution to journalArticle

Franklin, MC, Carey, KD, Vajdos, FF, Leahy, DJ, De Vos, AM & Sliwkowski, MX 2004, 'Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex', Cancer Cell, vol. 5, no. 4, pp. 317-328. https://doi.org/10.1016/S1535-6108(04)00083-2
Franklin MC, Carey KD, Vajdos FF, Leahy DJ, De Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004 Apr;5(4):317-328. https://doi.org/10.1016/S1535-6108(04)00083-2
Franklin, Matthew C. ; Carey, Kendall D. ; Vajdos, Felix F. ; Leahy, Daniel J. ; De Vos, Abraham M. ; Sliwkowski, Mark X. / Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. In: Cancer Cell. 2004 ; Vol. 5, No. 4. pp. 317-328.
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