Asset Details
Do you wish to reserve the book?
Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface
Hey, we have placed the reservation for you!
By the way, why not check out events that you can attend while you pick your title.
Oops! Something went wrong.
Looks like we were not able to place the reservation. Kindly try again later.
Are you sure you want to remove the book from the shelf?
Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface
Do you wish to request the book?
Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface
Please be aware that the book you have requested cannot be checked out. If you would like to checkout this book, you can reserve another copy
We have requested the book for you!
Your request is successful and it will be processed during the Library working hours. Please check the status of your request in My Requests.
Oops! Something went wrong.
Looks like we were not able to place your request. Kindly try again later.
Journal Article
Structures of the HER2–HER3–NRG1β complex reveal a dynamic dimer interface
2021
Overview
Human epidermal growth factor receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex
1
–
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 extracellular domain 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.
Cryo-electron microscopy structures of the HER2–HER3–NRG1β complex reveal a dynamic HER2–HER3 interface and explain the mechanism for the activating HER2 cancer mutations.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82/16
/ 82/80
/ 82/83
/ Antibodies, Monoclonal, Humanized - chemistry
/ Antibodies, Monoclonal, Humanized - ultrastructure
/ Binding
/ Dimers
/ Domains
/ Humanities and Social Sciences
/ Humans
/ Immunoglobulin Fab Fragments - chemistry
/ Ligands
/ Mutants
/ Mutation
/ Neuregulin-1 - ultrastructure
/ Receptor, ErbB-2 - chemistry
/ Receptor, ErbB-2 - ultrastructure
/ Receptor, ErbB-3 - chemistry
/ Receptor, ErbB-3 - ultrastructure
/ Science
