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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 9o58 | ||||||
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タイトル | Zymogen ADAM17-iRhom2 complex bound by the MEDI3622 Fab | ||||||
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![]() | IMMUNE SYSTEM / Inhibitor / Complex / Sheddase | ||||||
機能・相同性 | ![]() ADAM 17 endopeptidase / regulation of mast cell apoptotic process / positive regulation of epidermal growth factor-activated receptor activity / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / regulation of epidermal growth factor receptor signaling pathway / cellular response to high density lipoprotein particle stimulus / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing ...ADAM 17 endopeptidase / regulation of mast cell apoptotic process / positive regulation of epidermal growth factor-activated receptor activity / signal release / metalloendopeptidase activity involved in amyloid precursor protein catabolic process / regulation of epidermal growth factor receptor signaling pathway / cellular response to high density lipoprotein particle stimulus / production of molecular mediator involved in inflammatory response / Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant / Notch receptor processing / interleukin-6 receptor binding / tumor necrosis factor binding / protein transporter activity / positive regulation of T cell chemotaxis / TNF signaling / cytokine precursor processing / regulation of axon regeneration / positive regulation of leukocyte chemotaxis / metallodipeptidase activity / Release of Hh-Np from the secreting cell / Regulated proteolysis of p75NTR / commissural neuron axon guidance / regulation of neuron migration / positive regulation of tumor necrosis factor-mediated signaling pathway / neutrophil mediated immunity / germinal center formation / Notch binding / wound healing, spreading of epidermal cells / positive regulation of vascular endothelial cell proliferation / negative regulation of cold-induced thermogenesis / CD163 mediating an anti-inflammatory response / positive regulation of epidermal growth factor receptor signaling pathway / cell adhesion mediated by integrin / regulation of protein secretion / growth factor binding / Signaling by EGFR / amyloid precursor protein catabolic process / cytokine binding / Collagen degradation / membrane protein ectodomain proteolysis / positive regulation of blood vessel endothelial cell migration / negative regulation of protein secretion / positive regulation of G1/S transition of mitotic cell cycle / Constitutive Signaling by NOTCH1 HD Domain Mutants / Growth hormone receptor signaling / Nuclear signaling by ERBB4 / Activated NOTCH1 Transmits Signal to the Nucleus / spleen development / positive regulation of chemokine production / Notch signaling pathway / B cell differentiation / bioluminescence / protein localization to plasma membrane / generation of precursor metabolites and energy / PDZ domain binding / cell motility / phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of inflammatory response to antigenic stimulus / negative regulation of transforming growth factor beta receptor signaling pathway / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / metalloendopeptidase activity / protein processing / SH3 domain binding / Golgi lumen / epidermal growth factor receptor signaling pathway / metallopeptidase activity / positive regulation of tumor necrosis factor production / integrin binding / protein transport / T cell differentiation in thymus / peptidase activity / actin cytoskeleton / negative regulation of neuron projection development / positive regulation of cell growth / endopeptidase activity / response to lipopolysaccharide / response to hypoxia / cell adhesion / defense response to Gram-positive bacterium / positive regulation of cell migration / apical plasma membrane / membrane raft / response to xenobiotic stimulus / endoplasmic reticulum lumen / Golgi membrane / positive regulation of cell population proliferation / endoplasmic reticulum membrane / cell surface / proteolysis / metal ion binding / membrane / plasma membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | ![]() ![]() ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.53 Å | ||||||
![]() | Slone, C.E. / Maciag, J.J. | ||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex. 著者: Joseph J Maciag / Conner E Slone / Hala F Alnajjar / Maria F Rich / Bryce Guion / Igal Ifergan / Carl P Blobel / Tom C M Seegar / ![]() 要旨: The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic ...The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17-iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex. | ||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 301.1 KB | 表示 | ![]() |
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PDB形式 | ![]() | 232.6 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.9 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.9 MB | 表示 | |
XML形式データ | ![]() | 59 KB | 表示 | |
CIF形式データ | ![]() | 86.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 70127MC ![]() 9o54C M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-タンパク質 , 2種, 2分子 AB
#1: タンパク質 | 分子量: 91328.742 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#2: タンパク質 | 分子量: 84277.539 Da / 分子数: 1 / 由来タイプ: 組換発現 由来: (組換発現) ![]() ![]() ![]() 遺伝子: GFP, RHBDF2, IRHOM2, RHBDL5, RHBDL6 / 発現宿主: ![]() |
-抗体 , 2種, 2分子 CD
#3: 抗体 | 分子量: 23324.887 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#4: 抗体 | 分子量: 23442.270 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
-糖 , 2種, 7分子 
#5: 多糖 | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose |
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#6: 糖 | ChemComp-NAG / |
-非ポリマー , 2種, 2分子 


#7: 化合物 | ChemComp-CA / |
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#8: 化合物 | ChemComp-ZN / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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Has protein modification | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Zymogen ADA17-iRhom2 complex bound by the MEDI3622 Fab タイプ: COMPLEX / Entity ID: #2-#4 / 由来: RECOMBINANT |
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分子量 | 値: 0.23 MDa / 実験値: NO |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
試料 | 濃度: 5.3 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: TFS KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2200 nm / 最小 デフォーカス(公称値): 400 nm |
撮影 | 電子線照射量: 58.3 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
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解析
EMソフトウェア | 名称: PHENIX / バージョン: 1.20.1_4487 / カテゴリ: モデル精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.53 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 46753 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
精密化 | 最高解像度: 3.53 Å 立体化学のターゲット値: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS) | ||||||||||||||||||||||||
拘束条件 |
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