+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-10288 | |||||||||
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タイトル | structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes | |||||||||
マップデータ | ||||||||||
試料 |
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生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 5.0 Å | |||||||||
データ登録者 | Liu Y / Bunney T / Phillips C / Katan M | |||||||||
資金援助 | 英国, 1件
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引用 | ジャーナル: EBioMedicine / 年: 2020 タイトル: Structural insights and activating mutations in diverse pathologies define mechanisms of deregulation for phospholipase C gamma enzymes. 著者: Yang Liu / Tom D Bunney / Sakshi Khosa / Kévin Macé / Katharina Beckenbauer / Trevor Askwith / Sarah Maslen / Christopher Stubbs / Taiana M de Oliveira / Kasim Sader / Mark Skehel / Anne- ...著者: Yang Liu / Tom D Bunney / Sakshi Khosa / Kévin Macé / Katharina Beckenbauer / Trevor Askwith / Sarah Maslen / Christopher Stubbs / Taiana M de Oliveira / Kasim Sader / Mark Skehel / Anne-Claude Gavin / Christopher Phillips / Matilda Katan / 要旨: BACKGROUND: PLCγ enzymes are key nodes in cellular signal transduction and their mutated and rare variants have been recently implicated in development of a range of diseases with unmet need ...BACKGROUND: PLCγ enzymes are key nodes in cellular signal transduction and their mutated and rare variants have been recently implicated in development of a range of diseases with unmet need including cancer, complex immune disorders, inflammation and neurodegenerative diseases. However, molecular nature of activation and the impact and dysregulation mechanisms by mutations, remain unclear; both are critically dependent on comprehensive characterization of the intact PLCγ enzymes. 手法: For structural studies we applied cryo-EM, cross-linking mass spectrometry and hydrogen-deuterium exchange mass spectrometry. In parallel, we compiled mutations linked to main pathologies, ...手法: For structural studies we applied cryo-EM, cross-linking mass spectrometry and hydrogen-deuterium exchange mass spectrometry. In parallel, we compiled mutations linked to main pathologies, established their distribution and assessed their impact in cells and in vitro. FINDINGS: We define structure of a complex containing an intact, autoinhibited PLCγ1 and the intracellular part of FGFR1 and show that the interaction is centred on the nSH2 domain of PLCγ1. We ...FINDINGS: We define structure of a complex containing an intact, autoinhibited PLCγ1 and the intracellular part of FGFR1 and show that the interaction is centred on the nSH2 domain of PLCγ1. We define the architecture of PLCγ1 where an autoinhibitory interface involves the cSH2, spPH, TIM-barrel and C2 domains; this relative orientation occludes PLCγ1 access to its substrate. Based on this framework and functional characterization, the mechanism leading to an increase in PLCγ1 activity for the largest group of mutations is consistent with the major, direct impact on the autoinhibitory interface. INTERPRETATION: We reveal features of PLCγ enzymes that are important for determining their activation status. Targeting such features, as an alternative to targeting the PLC active site that has so ...INTERPRETATION: We reveal features of PLCγ enzymes that are important for determining their activation status. Targeting such features, as an alternative to targeting the PLC active site that has so far not been achieved for any PLC, could provide new routes for clinical interventions related to various pathologies driven by PLCγ deregulation. FUND: CR UK, MRC and AstaZeneca. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_10288.map.gz | 2.1 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-10288-v30.xml emd-10288.xml | 8.8 KB 8.8 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_10288.png | 69.8 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-10288 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-10288 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_10288_validation.pdf.gz | 204.6 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_10288_full_validation.pdf.gz | 203.7 KB | 表示 | |
XML形式データ | emd_10288_validation.xml.gz | 5.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-10288 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-10288 | HTTPS FTP |
-関連構造データ
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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-マップ
ファイル | ダウンロード / ファイル: emd_10288.map.gz / 形式: CCP4 / 大きさ: 15.6 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-試料の構成要素
-全体 : protein complex
全体 | 名称: protein complex |
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要素 |
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-超分子 #1: protein complex
超分子 | 名称: protein complex / タイプ: complex / ID: 1 / 親要素: 0 |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
組換発現 | 生物種: Mammalian 1 orthobornavirus (ウイルス) |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 8 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 検出モード: COUNTING / 平均電子線量: 0.5 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: DIFFRACTION |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
-画像解析
CTF補正 | ソフトウェア - 名称: Gctf (ver. 1.18) |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 5.0 Å / 解像度の算出法: FSC 0.143 CUT-OFF / ソフトウェア - 名称: RELION (ver. 3.0) / 使用した粒子像数: 155175 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD / ソフトウェア - 名称: RELION (ver. 3.0) |