Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface

Nature. 2021 Dec;600(7888):339-343. doi: 10.1038/s41586-021-04084-z. Epub 2021 Nov 10.


Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex1-3 upon binding of growth factor neuregulin-1β (NRG1β). The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. Here we isolated the NRG1β-bound near full-length HER2-HER3 dimer and, using cryo-electron microscopy, reconstructed the extracellulardomain module, revealing unexpected dynamics at the HER2-HER3 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. 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. 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. Our structure of the HER2(S310F)-HER3-NRG1β-trastuzumab Fab complex reveals that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, similar to oncogenic mutations, therapeutic agents exploit the intrinsic dynamics of the HER2-HER3 heterodimer. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Antibodies, Monoclonal, Humanized / chemistry
  • Antibodies, Monoclonal, Humanized / ultrastructure
  • Binding Sites
  • Cryoelectron Microscopy*
  • Humans
  • Immunoglobulin Fab Fragments / chemistry
  • Models, Molecular
  • Mutation
  • Neuregulin-1 / chemistry*
  • Neuregulin-1 / ultrastructure
  • Oncogenes / genetics
  • Protein Multimerization*
  • Protein Stability
  • Receptor, ErbB-2 / chemistry*
  • Receptor, ErbB-2 / ultrastructure
  • Receptor, ErbB-3 / chemistry*
  • Receptor, ErbB-3 / ultrastructure
  • Trastuzumab / chemistry
  • Trastuzumab / ultrastructure


  • Antibodies, Monoclonal, Humanized
  • Immunoglobulin Fab Fragments
  • NRG1 protein, human
  • Neuregulin-1
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • pertuzumab
  • Trastuzumab