+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6jr3 | ||||||||||||
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タイトル | Crystal structure of insulin hexamer fitted into cryo EM density map where each dimer was kept as rigid body | ||||||||||||
要素 |
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キーワード | HORMONE / Insulin fibrillation / Natural polyphenols / Anti-Amyloid activity / Insulin hexamer / Bioavailability | ||||||||||||
機能・相同性 | 機能・相同性情報 negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / Regulation of insulin secretion / negative regulation of protein catabolic process / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / regulation of synaptic plasticity / vasodilation / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / glucose metabolic process / regulation of protein localization / glucose homeostasis / insulin receptor signaling pathway / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of NF-kappaB transcription factor activity / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / Golgi membrane / endoplasmic reticulum lumen / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) | ||||||||||||
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: 14.5 Å | ||||||||||||
データ登録者 | Sengupta, J. / Pathak, B.K. / Bhakta, S. | ||||||||||||
資金援助 | インド, 3件
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引用 | ジャーナル: J Comput Aided Mol Des / 年: 2020 タイトル: Resveratrol as a nontoxic excipient stabilizes insulin in a bioactive hexameric form. 著者: Bani Kumar Pathak / Debajyoti Das / Sayan Bhakta / Partha Chakrabarti / Jayati Sengupta / 要旨: Insulin aggregation is the leading cause of considerable reduction in the amount of active drug molecules in liquid formulations manufactured for diabetes management. Phenolic compounds, such as ...Insulin aggregation is the leading cause of considerable reduction in the amount of active drug molecules in liquid formulations manufactured for diabetes management. Phenolic compounds, such as phenol and m-cresol, are routinely used to stabilize insulin in a hexameric form during its commercial preparation. However, long term usage of commercial insulin results in various adverse secondary responses, for which toxicity of the phenolic excipients is primarily responsible. In this study we aimed to find out a nontoxic insulin stabilizer. To that end, we have selected resveratrol, a natural polyphenol, as a prospective nontoxic insulin stabilizer because of its structural similarity with commercially used phenolic compounds. Atomic force microscopy visualization of resveratrol-treated human insulin revealed that resveratrol has a unique ability to arrest hINS in a soluble oligomeric form having discrete spherical morphology. Most importantly, resveratrol-treated insulin is nontoxic for HepG2 cells and it effectively maintains low blood glucose in a mouse model. Cryo-electron microscopy revealed 3D morphology of resveratrol-stabilized insulin that strikingly resembles crystal structures of insulin hexamer formulated with m-cresol. Significantly, we found that, in a condition inductive to amyloid fibrillation at physiological pH, resveratrol is capable of stabilizing insulin more efficiently than m-cresol. Thus, this study describes resveratrol as an effective nontoxic natural molecule that can be used for stabilizing insulin in a bioactive oligomeric form during its commercial formulation. | ||||||||||||
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 | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 6jr3.cif.gz | 18.2 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6jr3.ent.gz | 8.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 6jr3.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 6jr3_validation.pdf.gz | 740.9 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 6jr3_full_validation.pdf.gz | 740.6 KB | 表示 | |
XML形式データ | 6jr3_validation.xml.gz | 12.8 KB | 表示 | |
CIF形式データ | 6jr3_validation.cif.gz | 17.8 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/jr/6jr3 ftp://data.pdbj.org/pub/pdb/validation_reports/jr/6jr3 | HTTPS FTP |
-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
#1: タンパク質・ペプチド | 分子量: 2383.698 Da / 分子数: 6 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: INS / 発現宿主: Saccharomyces cerevisiae (パン酵母) / 参照: UniProt: P01308 #2: タンパク質・ペプチド | 分子量: 3433.953 Da / 分子数: 6 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: INS / 発現宿主: Saccharomyces cerevisiae (パン酵母) / 参照: UniProt: P01308 |
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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 |
-試料調製
構成要素 | 名称: Insulin oligomer and Resveratrol complex / タイプ: COMPLEX / Entity ID: all / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Saccharomyces cerevisiae (パン酵母) |
緩衝液 | pH: 7.4 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R2/2 |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
実験機器 | モデル: Tecnai Polara / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI POLARA 300 |
電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
試料ホルダ | 凍結剤: NITROGEN |
撮影 | 電子線照射量: 10 e/Å2 / フィルム・検出器のモデル: FEI EAGLE (4k x 4k) |
画像スキャン | 横: 4096 / 縦: 4096 |
-解析
EMソフトウェア | 名称: SPIDER / カテゴリ: 3次元再構成 |
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CTF補正 | タイプ: PHASE FLIPPING ONLY |
3次元再構成 | 解像度: 14.5 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 11000 / 対称性のタイプ: POINT |
原子モデル構築 | PDB-ID: 1EV6 Accession code: 1EV6 / Source name: PDB / タイプ: experimental model |