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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Structure of human oligosaccharyltransferase OST-A complex bound to NGI-1 | |||||||||
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![]() | N-glycosylation / OST-A complex / NGI-1 inhibitor / TRANSFERASE | |||||||||
機能・相同性 | ![]() oligosaccharyltransferase complex binding / oligosaccharyltransferase I complex / oligosaccharyltransferase III complex / Asparagine N-linked glycosylation / membrane-bounded organelle / co-translational protein modification / oligosaccharyltransferase complex / dolichyl-diphosphooligosaccharide-protein glycotransferase / dolichyl-diphosphooligosaccharide-protein glycotransferase activity / protein N-linked glycosylation via asparagine ...oligosaccharyltransferase complex binding / oligosaccharyltransferase I complex / oligosaccharyltransferase III complex / Asparagine N-linked glycosylation / membrane-bounded organelle / co-translational protein modification / oligosaccharyltransferase complex / dolichyl-diphosphooligosaccharide-protein glycotransferase / dolichyl-diphosphooligosaccharide-protein glycotransferase activity / protein N-linked glycosylation via asparagine / protein N-linked glycosylation / epithelial cell apoptotic process / azurophil granule membrane / protein glycosylation / Advanced glycosylation endproduct receptor signaling / blastocyst development / SRP-dependent cotranslational protein targeting to membrane / post-translational protein modification / rough endoplasmic reticulum / enzyme activator activity / T cell activation / response to endoplasmic reticulum stress / response to cytokine / protein modification process / regulation of protein stability / melanosome / Maturation of spike protein / nuclear body / inflammatory response / intracellular membrane-bounded organelle / endoplasmic reticulum membrane / Neutrophil degranulation / negative regulation of apoptotic process / apoptotic process / endoplasmic reticulum / protein-containing complex / RNA binding / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.61 Å | |||||||||
![]() | Ramirez AS / Kowal J / Locher KP | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB. 著者: Benjamin L Lampson / Ana S Ramίrez / Marta Baro / Lixia He / Mudra Hegde / Vidyasagar Koduri / Jamie L Pfaff / Ruth E Hanna / Julia Kowal / Nitin H Shirole / Yanfeng He / John G Doench / ...著者: Benjamin L Lampson / Ana S Ramίrez / Marta Baro / Lixia He / Mudra Hegde / Vidyasagar Koduri / Jamie L Pfaff / Ruth E Hanna / Julia Kowal / Nitin H Shirole / Yanfeng He / John G Doench / Joseph N Contessa / Kaspar P Locher / William G Kaelin / ![]() ![]() 要旨: Nuclear factor κB (NF-κB) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-κB via specific receptors. Using whole-genome ...Nuclear factor κB (NF-κB) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-κB via specific receptors. Using whole-genome CRISPR-Cas9 screens of LPS-treated cells that express an NF-κB-driven suicide gene, we discovered that the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization. The tool compound NGI-1 inhibits OST complexes in vivo, but the underlying molecular mechanism remained unknown. We did a CRISPR base-editor screen for NGI-1-resistant variants of STT3A, the catalytic subunit of OST-A. These variants, in conjunction with cryoelectron microscopy studies, revealed that NGI-1 binds the catalytic site of STT3A, where it traps a molecule of the donor substrate dolichyl-PP-GlcNAc-Man-Glc, suggesting an uncompetitive inhibition mechanism. Our results provide a rationale for and an initial step toward the development of STT3A-specific inhibitors and illustrate the power of contemporaneous base-editor and structural studies to define drug mechanism of action. | |||||||||
履歴 |
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構造の表示
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-EMDBアーカイブ
マップデータ | ![]() | 483.4 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 25.8 KB 25.8 KB | 表示 表示 | ![]() |
画像 | ![]() | 86.8 KB | ||
Filedesc metadata | ![]() | 8.6 KB | ||
その他 | ![]() ![]() | 475.7 MB 475.7 MB | ||
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 | ![]() 8pn9MC M: このマップから作成された原子モデル 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
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 0.648 Å | ||||||||||||||||||||
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_17779_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_17779_half_map_2.map | ||||||||||||
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投影像・断面図 |
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試料の構成要素
+全体 : OLIGOSACCHARYLTRANSFERASE COMPLEX OST-A WITH BOUND NGI-1 INHIBITOR
+超分子 #1: OLIGOSACCHARYLTRANSFERASE COMPLEX OST-A WITH BOUND NGI-1 INHIBITOR
+分子 #1: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase su...
+分子 #2: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase su...
+分子 #3: Transmembrane protein 258
+分子 #4: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase su...
+分子 #5: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase su...
+分子 #6: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase su...
+分子 #7: Oligosaccharyltransferase complex subunit OSTC
+分子 #8: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48...
+分子 #13: (2~{S},3~{R},4~{R},5~{S},6~{S})-2-(hydroxymethyl)-6-[(1~{S},2~{R}...
+分子 #14: (4R,7R)-4-hydroxy-N,N,N-trimethyl-4,9-dioxo-7-[(undecanoyloxy)met...
+分子 #15: MANGANESE (II) ION
+分子 #16: (2E,6E,10E,14E,18E,22E,26E)-3,7,11,15,19,23,27,31-OCTAMETHYLDOTRI...
+分子 #17: 5-(dimethylsulfamoyl)-~{N}-(5-methyl-1,3-thiazol-2-yl)-2-pyrrolid...
+分子 #18: water
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE-PROPANE |
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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: GATAN K3 (6k x 4k) / 平均電子線量: 54.2 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.4 µm / 最小 デフォーカス(公称値): 0.6 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
初期モデル | モデルのタイプ: PDB ENTRY PDBモデル - PDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 3.61 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 101699 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: ANGULAR RECONSTITUTION |