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

Hyun Soo Cho; Karen Mason; Kasra X. Ramyar; Ann Marie Stanley; Sandra B. Gabelli; Dan W. Denney; Daniel J. Leahy

doi:10.1038/nature01392

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

Hyun Soo Cho, Karen Mason, Kasra X. Ramyar, Ann Marie Stanley, Sandra B. Gabelli, Dan W. Denney, Daniel J. Leahy

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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). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. 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 cancer. 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.

Original language	English
Pages (from-to)	756-760
Number of pages	5
Journal	Nature
Volume	421
Issue number	6924
DOIs	https://doi.org/10.1038/nature01392
Publication status	Published - 2003 Feb 13

Bibliographical note

Funding Information:
Acknowledgements 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.

Funding Information:
Acknowledgements This work was supported by a Cancer Research UK programme grant, the Medical Research Council and by an EMBO Long-Term Fellowship (S.E.-M.). We thank S. Martin, V. M. Lee, R. Kypta, B. M. Gumbiner, P. Aspenström, I. Näthke and C. von Eichel-Streiber for plasmids and reagents.

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@article{130a751590dd495785a018279efb91a1,

title = "Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab",

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). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. 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 cancer. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 {\AA} and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 {\AA}. 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.",

author = "Cho, {Hyun Soo} and Karen Mason and Ramyar, {Kasra X.} and Stanley, {Ann Marie} and Gabelli, {Sandra B.} and Denney, {Dan W.} and Leahy, {Daniel J.}",

note = "Funding Information: Acknowledgements 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. Funding Information: Acknowledgements This work was supported by a Cancer Research UK programme grant, the Medical Research Council and by an EMBO Long-Term Fellowship (S.E.-M.). We thank S. Martin, V. M. Lee, R. Kypta, B. M. Gumbiner, P. Aspenstr{\"o}m, I. N{\"a}thke and C. von Eichel-Streiber for plasmids and reagents.",

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T1 - Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab

AU - Cho, Hyun Soo

AU - Mason, Karen

AU - Ramyar, Kasra X.

AU - Stanley, Ann Marie

AU - Gabelli, Sandra B.

AU - Denney, Dan W.

AU - Leahy, Daniel J.

N1 - Funding Information: Acknowledgements 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. Funding Information: Acknowledgements This work was supported by a Cancer Research UK programme grant, the Medical Research Council and by an EMBO Long-Term Fellowship (S.E.-M.). We thank S. Martin, V. M. Lee, R. Kypta, B. M. Gumbiner, P. Aspenström, I. Näthke and C. von Eichel-Streiber for plasmids and reagents.

PY - 2003/2/13

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N2 - 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). ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues, and their inappropriate activation is associated with the development and severity of many cancers. Overexpression of HER2 is found in 20-30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis. 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 cancer. 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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Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab

Abstract

Bibliographical note

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