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Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab

Author

Listed:
  • Hyun-Soo Cho

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Medicine)

  • Karen Mason

    (Genitope Corporation)

  • Kasra X. Ramyar

    (The Johns Hopkins University School of Medicine)

  • Ann Marie Stanley

    (The Johns Hopkins University School of Medicine)

  • Sandra B. Gabelli

    (The Johns Hopkins University School of Medicine)

  • Dan W. Denney

    (Genitope Corporation)

  • Daniel J. Leahy

    (The Johns Hopkins University School of Medicine
    The Johns Hopkins University School of Medicine)

Abstract

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4)1. ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues2, and their inappropriate activation is associated with the development and severity of many cancers3. Overexpression of HER2 is found in 20–30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis4. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer5. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 Å and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 Å. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.

Suggested Citation

  • Hyun-Soo Cho & Karen Mason & Kasra X. Ramyar & Ann Marie Stanley & Sandra B. Gabelli & Dan W. Denney & Daniel J. Leahy, 2003. "Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab," Nature, Nature, vol. 421(6924), pages 756-760, February.
    • Handle: RePEc:nat:nature:v:421:y:2003:i:6924:d:10.1038_nature01392
    DOI: 10.1038/nature01392
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    Cited by:

    1. Claudia L. Driscoll & Anthony H. Keeble & Mark R. Howarth, 2024. "SpyMask enables combinatorial assembly of bispecific binders," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Carmen Peess & Leopold von Proff & Sabine Goller & Karl Andersson & Michael Gerg & Magnus Malmqvist & Birgit Bossenmaier & Michael Schräml, 2015. "Deciphering the Stepwise Binding Mode of HRG1β to HER3 by Surface Plasmon Resonance and Interaction Map," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-13, February.
    3. Y-h Taguchi, 2017. "Tensor decomposition-based unsupervised feature extraction applied to matrix products for multi-view data processing," PLOS ONE, Public Library of Science, vol. 12(8), pages 1-36, August.
    4. Harish Shankaran & Yi Zhang & Yunbing Tan & Haluk Resat, 2013. "Model-Based Analysis of HER Activation in Cells Co-Expressing EGFR, HER2 and HER3," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-15, August.
    5. Mary S. Morrison & Tina Wang & Aditya Raguram & Colin Hemez & David R. Liu, 2021. "Disulfide-compatible phage-assisted continuous evolution in the periplasmic space," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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