Structural basis for negative cooperativity in growth factor binding to an EGF receptor. Insights into ErbB signaling from the structure of the ErbB2–pertuzumab complex. Comprehensive molecular portraits for human breast tumours. HER2 somatic mutations are associated with poor survival in HER2-negative breast cancers. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor. Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Extracellular domains drive homo- but not hetero- dimerization of erbB receptors. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Cryo-EM Structure of HER2–trastuzumab–pertuzumab complex. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. A single ligand is sufficient to activate EGFR dimers. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains.
Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Structure of the extracellular region of HER3 reveals an interdomain tether. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. EGF activates its receptor by removing interactions with autoinhibit ectodomain dimerization. Structural analysis of the EGFR/HER3 heterodimer reveals the molecular basis for activating HER3 mutations. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
Zhang, X., Gureasko, J., Shen, K., Cole, P. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Biochemical characterization of the protein tyrosine kinase domain of the ErbB3 (HER3) receptor protein. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. The unique features of a singly liganded HER2–HER3 heterodimer underscore the allosteric sensing of ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via a canonical active dimer interface.
Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2–HER3 heterodimer. Our structure of the HER2(S310F)–HER3–NRG1β–trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Both HER2–HER3 and HER2(S310F)–HER3 retain the capacity to bind to the HER2-directed therapeutic antibody trastuzumab, but the mutant complex does not bind to pertuzumab. In a structure of the oncogenic extracellular domain mutant HER2(S310F), we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved because the apo HER2 monomer does not undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm-binding pocket. Here we isolated the NRG1β-bound near full-length HER2–HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellular domain module, revealing unexpected dynamics at the HER2–HER3 dimerization interface.
The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex 1, 2, 3 upon binding of growth factor neuregulin-1β (NRG1β).