The major peak at ~14 ml elution volume is marked grey and corresponds to the fractions used for structural studies. c, Representative size exclusion chromatography profile of the HER2/HER3/NRG1β complex resolved on a Superose6 10/300 Increase column (GE Healthcare). The gel is representative of three independent experiments. b, A representative Coomassie-stained SDS-PAGE gel analysis of the HER2/HER3/NRG1β complex after purification showing bands corresponding to the HER2 and HER3 receptors. The Author(s), under exclusive licence to Springer Nature Limited.Ī, Schematic summary of the HER2/HER3/NRG1β complex purification strategy. 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 extracellulardomain 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. If you're interested in translating regularly as part of the LN Team, check out the application details on our About / Recruitment page.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). Submissions reposting someone else's work without permission will be denied. Please do not copy unofficial translations from other sites. Submissions from translation services will be denied. Please do not submit auto-translated content. You can join the LN Community and meet other translators on our Discord. ☆ Please note: If accepted, your translation will be credited as an LN Community submission, where other members can provide input and submit improvements. * What is the source of your translation? (Personal, subtitles, etc.) Please ensure that the number of lines in each paragraph match the original lyrics whenever possible. If you are interested in becoming a community translation checker for your language, please get in touch via our official Discord!) (If your language is not listed, we are currently unable to accept it at this time. Oh pretty please I promise one last chance Uh ![]() My head is still spinning, the verge of explodingīut now my heart is still naked…Ah, help meĬause this is only driving me to full on panic!īut nothing that I seem to do ever bothers you I hope you don’t find out the things I’m shy about Well we both know the answer now, wouldn’t you agree? Am I your type? Do you like it? Ah, darlingīut I am guessing it is the same for you and me
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