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.
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We thank C. Ogata and M. Becker for assistance at beamlines X4A and X25, respectively, of NSLS at Brookhaven National Laboratory; A. Ullrich for supplying a human HER2 complementary DNA; P. Longo for technical assistance; T. Garrett, S. Yokoyama and colleagues for supplying preprints in advance of publication; S. Yokoyama for coordinates of the EGF–EGFR complex; M. Lemmon, K. Ferguson, M. Amzel, J. Berg, S. Bouyain and W. Yang for discussion and comments on the manuscript; A. Guarne for help with figures; and N. Davidson for assistance with Herceptin. This work was supported by the NIH and the HHMI.
The authors declare that they have no competing financial interests.
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