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Structure Of The Extracellular Region Of HER2 Alone And In Complex With The Herceptin Fab
Hyun-Soo Cho, K. Mason, K. Ramyar, A. Stanley, S. Gabelli, D. Denney, D. Leahy
Published 2003 · Medicine, Biology
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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.
This paper references
Untangling the ErbB signalling network
Y. Yarden (2001)
Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein.
S. Munemitsu (1995)
Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.
D. Slamon (1987)
Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains
H. Ogiso (2002)
Dimerization of the p185neu transmembrane domain is necessary but not sufficient for transformation
C. L. Burke (1997)
Cellular phosphorylation of tau by GSK-3 beta influences tau binding to microtubules and microtubule organisation.
U. Wagner (1996)
The promise and perils of Wnt signaling through beta-catenin.
R. Moon (2002)
Hormones and Signaling
B. O'Malley (1998)
A program to produce both detailed and schematic plots of protein structures
P. Kraulis (1991)
GSK-3: new thoughts on an old enzyme.
D. M. Ferkey (2000)
e-mail: email@example.com). Coordinates and structure factors are available from the Protein Data Bank under accession numbers 1N8Y (rat sHER2) and 1N8Z (human sHER2–Herceptin Fab complex)
Inhibition of GSK-3 β leading to the loss of phosphorylated MAP-1 B is an early event in axonal remodelling induced by WNT-7 a or lithium
F. Lucas (1998)
Molecular Biology and Cell Biology
Andrey S Krasilnikov
Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos
X. He (1995)
Crystallography & NMR system: A new software suite for macromolecular structure determination.
A. Brünger (1998)
VL:VH domain rotations in engineered antibodies: Crystal structures of the Fab fragments from two murine antitumor antibodies and their engineered human constructs
M. Banfield (1997)
Molecular mechanisms underlying ErbB2/HER2 action in breast cancer
D. Harari (2000)
Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether
Hyun-Soo Cho (2002)
Improved methods for building protein models in electron density maps and the location of errors in these models.
T. Jones (1991)
Cell-Extracellular Matrix Interactions Stimulate the AP-1 Transcription Factor in an Integrin-Linked Kinase- and Glycogen Synthase Kinase 3-Dependent Manner
A. Troussard (1999)
Regulation of Spemann organizer formation by the intracellular kinase Xgsk-3.
S. Pierce (1995)
Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells.
M. Molina (2001)
Rho GTPases in cell biology
S. Etienne-Manneville (2002)
W. A. Wooster (1972)
APC binds to the novel protein EB1.
L. Su (1995)
Insulin receptor substrate2 phosphorylation is necessary for protein kinase C z activation by insulin in L 6 hIR cells
F. Oriente (2001)
erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells.
P. D. Di Fiore (1987)
Regulation of GSK-3 A Cellular Multiprocessor
A. Harwood (2001)
Binding specificities and affinities of egf domains for ErbB receptors
J. T. Jones (1999)
Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation
J. Zumbrunn (2001)
Role of glycogen synthase kinase 3 beta as a negative regulator of dorsoventral axis formation in Xenopus embryos.
I. Dominguez (1995)
CDC-42 controls early cell polarity and spindle orientation in C. elegans
M. Gotta (2001)
GSK 3 β / shaggy mediates patterning along the animal-vegetal axis of the sea urchin embryo
F. Emily-Fenouil (1998)
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
D. Slamon (2001)
Receptors for epidermal growth factor and other polypeptide mitogens.
G. Carpenter (1987)
CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans
A. Kay (2001)
PROCHECK: a program to check the stereochemical quality of protein structures
R. Laskowski (1993)
Herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells
M A Molina (2001)
Wnt signaling and cancer.
P. Polakis (2000)
The ErbB signaling network: receptor heterodimerization in development and cancer
M. Olayioye (2000)
Integrin-Mediated Activation of Cdc42 Controls Cell Polarity in Migrating Astrocytes through PKCζ
Sandrine Etienne-Manneville (2001)
M Carson (1997)
Dissecting interactions between EB1, microtubules and APC in cortical clusters at the plasma membrane.
A. Barth (2002)
Use of TLS parameters to model anisotropic displacements in macromolecular refinement.
M. Winn (2001)
Binding of GSK3β to the APC-β-Catenin Complex and Regulation of Complex Assembly
B. Rubinfeld (1996)
Jr Gene amplification methods. US patent 5
D W Denney (1998)
EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization.
K. Ferguson (2003)
Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics*
A. Berezov (2002)
EGF activates its receptor by relieving autoinhibition of ectodomain dimerization
K. M. Ferguson
Competing interests statement The authors declare that they have no competing financial interests
Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin).
M. Sliwkowski (1999)
Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization
M. Nakamura (2001)
The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parallel arrays of microtubule bundles in highly polarized epithelial cells
M. Mogensen (2002)
The subcellular destinations of apc proteins
M. Bienz (2002)
Intercellular junctions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity.
S. Ohno (2001)
AMoRe: an automated package for molecular replacement
J. Navaza (1994)
Jr Gene amplification methods
D. W. Denney (1998)
Cell Signaling by Receptor Tyrosine Kinases
J. Schlessinger (2000)
MOLREP: an Automated Program for Molecular Replacement
A. Vagin (1997)
Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor α
T. J. Garrett (2002)
Axin and Frat 1 interact with Dvl and GSK , bridging Dvl to GSK in the Wntmediated regulation of LEF1
L. Li (1999)
Supplementary Information accompanies the paper on Nature's website (ç http://www.nature.com/nature)
EGF activates its receptor by relieving auto-inhibition of ectodomain dimerization
K M Ferguson
EGF Family Receptors and Their Ligands in Human Cancer
C. Tang (1998)
A mammalian expression vector for expression and purification of secreted proteins for structural studies.
D. Leahy (2000)
Shape complementarity at protein–protein interfaces
R. Norel (1994)
This paper is referenced by
Immunohistochemical Study of HER 2 / neu Overexpression in Adenoid Cystic Carcinoma of Salivary Glands
J. Salehinejad (2014)
The functional capacity of the natural amino acids for molecular recognition.
S. Birtalan (2010)
Epidermal growth factor receptor (EGFR) signaling in cancer.
N. Normanno (2006)
A monoclonal antibody targeting ErbB2 domain III inhibits ErbB2 signaling and suppresses the growth of ErbB2-overexpressing breast tumors
Y. Meng (2016)
Clinical development of CAR T cell therapy in China: 2020 update.
Jianshu Wei (2020)
Value and limitations of measuring HER-2 extracellular domain in the serum of breast cancer patients.
A. Leary (2009)
Site-specific coupling and sterically controlled formation of multimeric antibody fab fragments with unnatural amino acids.
B. M. Hutchins (2011)
Conformational and Colloidal Stabilities of Isolated Constant Domains of Human Immunoglobulin G and Their Impact on Antibody Aggregation under Acidic Conditions.
Seiki Yageta (2015)
Functional Role of Membrane Lipids in EGF Receptor Dynamics and Regulation
M. Grzybek (2014)
Conformational HER-2/neu B-cell Epitope Peptide Vaccine Designed to Incorporate Two Native Disulfide Bonds Enhances Tumor Cell Binding and Antitumor Activities*
N. Dakappagari (2005)
Active and inactive conformations of the epidermal growth factor receptor.
K. Ferguson (2004)
Anti-HER 2 vaccines : new prospects for breast cancer therapy
M. Z. Ladjemi (2017)
High-Throughput Quantification of Surface Protein Internalization and Degradation.
Jakob C Stüber (2019)
Aglycosylated antibodies and antibody fragments produced in a scalable in vitro transcription-translation system
G. Yin (2012)
Elucidating Molecular Mechanisms of ERBB2/Neu-Induced Mammary Tumorigenesis
M. Landis (2006)
HER2 specific tumor targeting with dendrimer conjugated anti-HER2 mAb.
R. Shukla (2006)
HER2+ breast cancer: review of biologic relevance and optimal use of diagnostic tools.
D. Hicks (2008)
A molecular view of anti-ErbB monoclonal antibody therapy.
D. Leahy (2008)
Novel anticancer targets: revisiting ERBB2 and discovering ERBB3
J. Baselga (2009)
Therapeutic Antibodies in Clinical Use and Leading Clinical Candidates
Ningyan Zhang (2009)
Amplification of the Oncogene HER2 in Breast Cancer: Molecular Basis and Therapeutic Significance
Francini Matos Lima Lin (2012)
Direct identification of ligand-receptor interactions on living cells and tissues
Andreas P. Frei (2012)
Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbBLigands and Remain Dependent on the ErbBReceptor Network
C. Ritter (2007)
Will Single-Time Tumor Profiling and a ‘ ‘ Guilt by Association ’ ’ ApproachAllowUs toOutsmartHER 2-PositiveBreastCancer ? 55
C. Arteaga (2007)
The improvement of an anti-CD22 immunotoxin
Seiji Kawa (2011)
Antitumor activity of HER-2 inhibitors.
S. Rabindran (2005)
Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children
M. Merker (2017)
Rational design of a humanized glucagon-like peptide-1 receptor agonist antibody.
Y. Zhang (2015)
Impact of target antigen properties on antibody effector mechanisms
K. Cleary (2015)
Targeting HER2 signaling pathway for radiosensitization: Alternative strategy for therapeutic resistance
Mina No (2009)
Regulation and New Treatment Strategies in Breast Cancer.
Rosa-Maria Ferraiuolo (2019)
Antibody–Antigen Recognition and Conformational Changes
R. Stanfield (2010)See more