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基本情報
登録情報 | データベース: PDB / ID: 7ure | |||||||||
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タイトル | Human PORCN in complex with palmitoleoylated WNT3A peptide | |||||||||
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![]() | TRANSFERASE/TRANSFERASE INHIBITOR / product-bound / complex / TRANSFERASE / TRANSFERASE-TRANSFERASE PRODUCT complex / TRANSFERASE-TRANSFERASE INHIBITOR complex | |||||||||
機能・相同性 | ![]() [Wnt protein] O-palmitoleoyl transferase / Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / LGK974 inhibits PORCN / protein palmitoleylation / positive regulation of collateral sprouting in absence of injury / palmitoleoyltransferase activity / positive regulation of mesodermal cell fate specification ...[Wnt protein] O-palmitoleoyl transferase / Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / LGK974 inhibits PORCN / protein palmitoleylation / positive regulation of collateral sprouting in absence of injury / palmitoleoyltransferase activity / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / cell proliferation in midbrain / spinal cord association neuron differentiation / Formation of the posterior neural plate / Wnt protein secretion / lipid modification / COP9 signalosome assembly / protein lipidation / Wnt-Frizzled-LRP5/6 complex / positive regulation of cell-cell adhesion mediated by cadherin / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / synaptic vesicle recycling / Signaling by RNF43 mutants / WNT ligand biogenesis and trafficking / glycoprotein metabolic process / positive regulation of cardiac muscle cell differentiation / cell proliferation in forebrain / negative regulation of axon extension involved in axon guidance / secondary palate development / Specification of the neural plate border / somatic stem cell division / non-canonical Wnt signaling pathway / co-receptor binding / cardiac muscle cell fate commitment / presynapse assembly / positive regulation of skeletal muscle tissue development / Wnt-protein binding / negative regulation of dopaminergic neuron differentiation / midbrain dopaminergic neuron differentiation / dorsal/ventral neural tube patterning / regulation of postsynapse to nucleus signaling pathway / mammary gland development / post-anal tail morphogenesis / frizzled binding / positive regulation of neural precursor cell proliferation / positive regulation of hepatocyte proliferation / Class B/2 (Secretin family receptors) / Disassembly of the destruction complex and recruitment of AXIN to the membrane / myoblast differentiation / inner ear morphogenesis / cell fate commitment / regulation of synapse organization / negative regulation of fat cell differentiation / B cell proliferation / fat cell differentiation / heart looping / Formation of paraxial mesoderm / skeletal muscle cell differentiation / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of receptor internalization / AMPA glutamate receptor complex / hemopoiesis / regulation of presynapse assembly / Transcriptional and post-translational regulation of MITF-M expression and activity / canonical Wnt signaling pathway / regulation of microtubule cytoskeleton organization / cellular response to retinoic acid / positive regulation of B cell proliferation / Regulation of FZD by ubiquitination / positive regulation of protein localization to plasma membrane / extracellular matrix organization / positive regulation of cytokine production / TCF dependent signaling in response to WNT / cytokine activity / axon guidance / hippocampus development / modulation of chemical synaptic transmission / neuron differentiation / Wnt signaling pathway / platelet aggregation / negative regulation of neurogenesis / Golgi lumen / osteoblast differentiation / positive regulation of canonical Wnt signaling pathway / endocytic vesicle membrane / positive regulation of peptidyl-serine phosphorylation / protein localization / negative regulation of neuron projection development / early endosome membrane / presynapse / heart development / transcription coactivator activity / in utero embryonic development / cell population proliferation / transcription by RNA polymerase II / receptor ligand activity / positive regulation of protein phosphorylation / protein domain specific binding / endoplasmic reticulum lumen / signaling receptor binding 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: 3.19 Å | |||||||||
![]() | Liu, Y. / Qi, X. / Li, X. | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Mechanisms and inhibition of Porcupine-mediated Wnt acylation. 著者: Yang Liu / Xiaofeng Qi / Linda Donnelly / Nadia Elghobashi-Meinhardt / Tao Long / Rich W Zhou / Yingyuan Sun / Boyuan Wang / Xiaochun Li / ![]() ![]() 要旨: Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires ...Wnt signalling is essential for regulation of embryonic development and adult tissue homeostasis, and aberrant Wnt signalling is frequently associated with cancers. Wnt signalling requires palmitoleoylation on a hairpin 2 motif by the endoplasmic reticulum-resident membrane-bound O-acyltransferase Porcupine (PORCN). This modification is indispensable for Wnt binding to its receptor Frizzled, which triggers signalling. Here we report four cryo-electron microscopy structures of human PORCN: the complex with the palmitoleoyl-coenzyme A (palmitoleoyl-CoA) substrate; the complex with the PORCN inhibitor LGK974, an anti-cancer drug currently in clinical trials; the complex with LGK974 and WNT3A hairpin 2 (WNT3Ap); and the complex with a synthetic palmitoleoylated WNT3Ap analogue. The structures reveal that hairpin 2 of WNT3A, which is well conserved in all Wnt ligands, inserts into PORCN from the lumenal side, and the palmitoleoyl-CoA accesses the enzyme from the cytosolic side. The catalytic histidine triggers the transfer of the unsaturated palmitoleoyl group to the target serine on the Wnt hairpin 2, facilitated by the proximity of the two substrates. The inhibitor-bound structure shows that LGK974 occupies the palmitoleoyl-CoA binding site to prevent the reaction. Thus, this work provides a mechanism for Wnt acylation and advances the development of PORCN inhibitors for cancer treatment. | |||||||||
履歴 |
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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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PDBx/mmCIF形式 | ![]() | 136.3 KB | 表示 | ![]() |
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PDB形式 | ![]() | 103.6 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
関連構造データ | ![]() 26710MC ![]() 7uraC ![]() 7urcC ![]() 7urdC ![]() 7urfC 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
-Isoform 2 of ... , 2種, 2分子 AB
#1: タンパク質 | 分子量: 52824.652 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: Q9H237, [Wnt protein] O-palmitoleoyl transferase |
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#4: タンパク質・ペプチド | 分子量: 2529.059 Da / 分子数: 1 / Fragment: residues 199-220 / 由来タイプ: 合成 / 由来: (合成) ![]() |
-抗体 , 2種, 2分子 LH
#2: 抗体 | 分子量: 25673.693 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
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#3: 抗体 | 分子量: 26933.135 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
-非ポリマー , 3種, 3分子 ![](data/chem/img/AJP.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/PAM.gif)
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![](data/chem/img/PAM.gif)
#5: 化合物 | ChemComp-AJP / |
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#6: 化合物 | ChemComp-ZN / |
#7: 化合物 | ChemComp-PAM / |
-詳細
研究の焦点であるリガンドがあるか | Y |
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-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 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||||||||
試料 | 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: FEI TITAN 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): 2000 nm / 最小 デフォーカス(公称値): 700 nm |
撮影 | 電子線照射量: 8.5 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.16_3549: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.19 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 113566 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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