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Allosteric activation of preformed EGF receptor dimers by a single ligand binding event
https://oist.repo.nii.ac.jp/records/2852
https://oist.repo.nii.ac.jp/records/2852c6cb6107-d155-41da-a33c-ec80eb179fb8
名前 / ファイル | ライセンス | アクション |
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fendo-13-1042787 (9.7 MB)
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CC BY 4.0
Creative Commons Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0/) |
Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2022-12-01 | |||||
タイトル | ||||||
タイトル | Allosteric activation of preformed EGF receptor dimers by a single ligand binding event | |||||
言語 | ||||||
言語 | eng | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | cancer biology | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | conformational change | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | cooperativity | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | cryo-electron tomography | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | receptor tyrosine kinase | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | signal transduction | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | single-molecule biophysics | |||||
キーワード | ||||||
主題Scheme | Other | |||||
主題 | transmembrane signaling | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者(英) |
Purba, Endang R.
× Purba, Endang R.× Saita, Ei-ichiro× Akhouri, Reetesh R.× Öfverstedt, Lars-Goran× Wilken, Gunnar× Skoglund, Ulf× Maruyama, Ichiro N. |
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書誌情報 |
en : Frontiers in Endocrinology 巻 13, 発行日 2022-11-30 |
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抄録 | ||||||
内容記述タイプ | Other | |||||
内容記述 | Aberrant activation of the epidermal growth factor receptor (EGFR) by mutations has been implicated in a variety of human cancers. Elucidation of the structure of the full-length receptor is essential to understand the molecular mechanisms underlying its activation. Unlike previously anticipated, here, we report that purified full-length EGFR adopts a homodimeric form in vitro before and after ligand binding. Cryo-electron tomography analysis of the purified receptor also showed that the extracellular domains of the receptor dimer, which are conformationally flexible before activation, are stabilized by ligand binding. This conformational flexibility stabilization most likely accompanies rotation of the entire extracellular domain and the transmembrane domain, resulting in dissociation of the intracellular kinase dimer and, thus, rearranging it into an active form. Consistently, mutations of amino acid residues at the interface of the symmetric inactive kinase dimer spontaneously activate the receptor in vivo. Optical observation also indicated that binding of only one ligand activates the receptor dimer on the cell surface. Our results suggest how oncogenic mutations spontaneously activate the receptor and shed light on the development of novel cancer therapies. | |||||
出版者 | ||||||
出版者 | Frontiers Media S.A. | |||||
ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 1664-2392 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | info:doi/10.3389/fendo.2022.1042787 | |||||
権利 | ||||||
権利情報 | © 2022 © 2022 Purba, Saita, Akhouri, Öfverstedt, Wilken, Skoglund and Maruyama. | |||||
関連サイト | ||||||
識別子タイプ | URI | |||||
関連識別子 | https://www.frontiersin.org/articles/10.3389/fendo.2022.1042787/full | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 |