7MN5

Structure of the HER2/HER3/NRG1b Heterodimer Extracellular Domain

Summary for 7MN5

• Entry DOI: 10.2210/pdb7mn5/pdb
• EMDB information: 23916
• Descriptor: Receptor tyrosine-protein kinase erbB-3, Isoform 6 of Pro-neuregulin-1, membrane-bound isoform, Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein, ... (6 entities in total)
• Functional Keywords: complex, receptor tyrosine kinase, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 290801.57

Authors

Diwanji, D.,Trenker, R.,Verba, K.A.,Jura, N. (deposition date: 2021-04-30, release date: 2021-10-27, Last modification date: 2024-11-13)

Primary citation

Diwanji, D.,Trenker, R.,Thaker, T.M.,Wang, F.,Agard, D.A.,Verba, K.A.,Jura, N.
Structures of the HER2-HER3-NRG1 beta complex reveal a dynamic dimer interface.
Nature, 600:339-343, 2021

PubMed Abstract: Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex 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.

PubMed: 34759323
DOI: 10.1038/s41586-021-04084-z

Experimental method

ELECTRON MICROSCOPY (2.93 Å)