National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM139635
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
1F30CA247147
United States
German Research Foundation (DFG)
TR 1668/1-1
Germany
Citation
Journal: Nature / Year: 2021 Title: Structures of the HER2-HER3-NRG1β complex reveal a dynamic dimer interface. Authors: Devan Diwanji / Raphael Trenker / Tarjani M Thaker / Feng Wang / David A Agard / Kliment A Verba / Natalia Jura / 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 ...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.
History
Deposition
Apr 30, 2021
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Header (metadata) release
Nov 10, 2021
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Map release
Nov 10, 2021
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Update
Dec 22, 2021
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Current status
Dec 22, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Entire : NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
Entire
Name: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in the context of near full-length receptors
Components
Complex: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in the context of near full-length receptors
Complex: Trastuzumab (Herceptin) Fab
Protein or peptide: Trastuzumab Fab Light Chain
Protein or peptide: Trastuzumab Fab Heavy Chain
Complex: Neuregulin-1b isoform 6
Protein or peptide: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
Complex: HER3
Protein or peptide: Receptor tyrosine-protein kinase erbB-3
Complex: HER2-S310F-MBP Fusion
Protein or peptide: Receptor tyrosine-protein kinase erbB-2,Maltose/maltodextrin-binding periplasmic protein
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
+
Supramolecule #1: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in...
Supramolecule
Name: NRG1b-bound HER2/HER3 Heterodimer bound to the Trastuzumab Fab in the context of near full-length receptors type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
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