+データを開く
-基本情報
登録情報 | データベース: SASBDB / ID: SASDE26 |
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試料 | Albumin-insulin degludec 1:12 complex
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機能・相同性 | 機能・相同性情報 exogenous protein binding / Ciprofloxacin ADME / enterobactin binding / cellular response to calcium ion starvation / Heme biosynthesis / HDL remodeling / negative regulation of mitochondrial depolarization / Prednisone ADME / Heme degradation / negative regulation of NAD(P)H oxidase activity ...exogenous protein binding / Ciprofloxacin ADME / enterobactin binding / cellular response to calcium ion starvation / Heme biosynthesis / HDL remodeling / negative regulation of mitochondrial depolarization / Prednisone ADME / Heme degradation / 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 / Aspirin ADME / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / antioxidant activity / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / toxic substance binding / regulation of protein localization to plasma membrane / fatty acid homeostasis / negative regulation of gluconeogenesis / negative regulation of lipid catabolic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Scavenging of heme from plasma / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / positive regulation of insulin receptor signaling pathway / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / nitric oxide-cGMP-mediated signaling / Recycling of bile acids and salts / positive regulation of protein autophosphorylation / insulin-like growth factor receptor binding / transport vesicle / Insulin receptor recycling / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / activation of protein kinase B activity / cellular response to starvation / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / platelet alpha granule lumen / positive regulation of nitric-oxide synthase activity / acute-phase response / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / cognition / Regulation of insulin secretion / endosome lumen / fatty acid binding / positive regulation of D-glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / Post-translational protein phosphorylation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / negative regulation of protein catabolic process / regulation of synaptic plasticity / hormone activity / Cytoprotection by HMOX1 / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / glucose metabolic process / Platelet degranulation / pyridoxal phosphate binding / cell-cell signaling / insulin receptor signaling pathway / positive regulation of NF-kappaB transcription factor activity / glucose homeostasis / regulation of protein localization / protein-folding chaperone binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / blood microparticle 類似検索 - 分子機能 |
引用 | ジャーナル: Acta Crystallogr D Struct Biol / 年: 2019 タイトル: Solution structures of long-acting insulin analogues and their complexes with albumin. 著者: Line A Ryberg / Pernille Sønderby / Fabian Barrientos / Jens T Bukrinski / Günther H J Peters / Pernille Harris / 要旨: The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of ...The lipidation of peptide drugs is one strategy to obtain extended half-lives, enabling once-daily or even less frequent injections for patients. The half-life extension results from a combination of self-association and association with human serum albumin (albumin). The self-association and association with albumin of two insulin analogues, insulin detemir and insulin degludec, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) in phenolic buffers. Detemir shows concentration-dependent self-association, with an equilibrium between hexamer, dihexamer, trihexamer and larger species, while degludec appears as a dihexamer independent of concentration. The solution structure of the detemir trihexamer has a bent shape. The stoichiometry of the association with albumin was studied using DLS. For albumin-detemir the molar stoichiometry was determined to be 1:6 (albumin:detemir ratio) and for albumin-degludec it was between 1:6 and 1:12 (albumin:degludec ratio). Batch SAXS measurements of a 1:6 albumin:detemir concentration series revealed a concentration dependence of complex formation. The data allowed the modelling of a complex between albumin and a detemir hexamer and a complex consisting of two albumins binding to opposite ends of a detemir dihexamer. Measurements of size-exclusion chromatography coupled to SAXS revealed a complex between a degludec dihexamer and albumin. Based on the results, equilibria for the albumin-detemir and albumin-degludec mixtures are proposed. |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-モデル
モデル #2469 | タイプ: atomic / 対称性: P1 / カイ2乗値: 1.741 Omokage検索でこの集合体の類似形状データを探す (詳細) |
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モデル #2470 | タイプ: dummy / ダミー原子の半径: 2.70 A / カイ2乗値: 1.665 / P-value: 0.000043 Omokage検索でこの集合体の類似形状データを探す (詳細) |
-試料
試料 | 名称: Albumin-insulin degludec 1:12 complex / 試料濃度: 6.5 mg/ml / Entity id: 1322 / 1323 |
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バッファ | 名称: 25 mM Na2HPO4, 15.9 mM m-cresol, 15.9 mM phenol, 212.8 mM glycerol, 20 mM NaCl pH: 7.6 |
要素 #1322 | タイプ: protein / 記述: Human Albumin (Recombumin(R) Elite, Albumedix Ltd.) / 分子量: 66.472 / 分子数: 1 / 参照: UniProt: P02768 配列: DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY APELLFFAKR YKAAFTECCQ ...配列: DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAKQRLKC ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK VHTECCHGDL LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI AEVENDEMPA DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ NCELFEQLGE YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH PEAKRMPCAE DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGL |
要素 #1323 | タイプ: protein / 記述: Insulin degludec(Tresiba(R), Novo Nordisk A/S) / 分子量: 6.1 / 分子数: 12 / 参照: UniProt: P01308 配列: GIVEQCCTSI CSLYQLENYC NFVNQHLCGS HLVEALYLVC GERGFFYTPK |
-実験情報
ビーム | 設備名称: PETRA III EMBL P12 / 地域: Hamburg / 国: Germany / 線源: X-ray synchrotron / 波長: 0.1241 Å / スペクトロメータ・検出器間距離: 3 mm | ||||||||||||||||||
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検出器 | 名称: Pilatus 2M | ||||||||||||||||||
スキャン | タイトル: Albumin-insulin degludec 1:12 complex / 測定日: 2017年6月27日 / セル温度: 20 °C / 照射時間: 1 sec. / 単位: 1/nm /
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距離分布関数 P(R) | ソフトウェア P(R): GNOM 5.0 / ポイント数: 747 /
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結果 | D max: 13.4 / カーブのタイプ: single_conc コメント: SEC–SAXS with flow cell, effective sample path length 1.7 mm, flow rate 0.70 mL/min, 100 µL sample loaded with concentration 10.6 mg/mL. A Superdex 200 Increase 10/300 GL column (GE ...コメント: SEC–SAXS with flow cell, effective sample path length 1.7 mm, flow rate 0.70 mL/min, 100 µL sample loaded with concentration 10.6 mg/mL. A Superdex 200 Increase 10/300 GL column (GE Healthcare Life Sciences) was used in combination with an Agilent 1260 Infinity Bio-Inert HPLC/FPLC machine Continuous 1 s SAXS data-frame measurements of SEC elution.
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