SASDEZ5: Albumin-insulin detemir 2:12 complex, P2 symmetry (Human Albumin ...

基本情報

• 登録情報: データベース: SASBDB / ID: SASDEZ5

試料

Albumin-insulin detemir 2:12 complex, P2 symmetry

• Human Albumin (Recombumin(R) Alpha, Albumedix Ltd.) (protein)
• Insulin detemir (Levemir(R), Novo Nordisk A/S) (protein)

機能・相同性

分子機能:

cellular response to calcium ion starvation / exogenous protein binding / Ciprofloxacin ADME / enterobactin binding / ヘム / 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 / regulation of cellular amino acid metabolic process / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / nitric oxide-cGMP-mediated signaling / IRS activation / Aspirin ADME / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / antioxidant activity / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / toxic substance binding / positive regulation of glycogen biosynthetic process / small molecule binding / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / positive regulation of nitric oxide mediated signal transduction / fatty acid homeostasis / regulation of protein localization to plasma membrane / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / Scavenging of heme from plasma / negative regulation of gluconeogenesis / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / positive regulation of insulin receptor signaling pathway / Recycling of bile acids and salts / 小胞 / 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 / cellular response to starvation / positive regulation of brown fat cell differentiation / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / activation of protein kinase B activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / platelet alpha granule lumen / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / Regulation of insulin secretion / acute-phase response / endosome lumen / fatty acid binding / positive regulation of protein secretion / positive regulation of glucose import / positive regulation of nitric-oxide synthase activity / positive regulation of cell differentiation / negative regulation of proteolysis / regulation of transmembrane transporter activity / Post-translational protein phosphorylation / wound healing / regulation of synaptic plasticity / insulin receptor binding / negative regulation of protein catabolic process / hormone activity / Cytoprotection by HMOX1 / 認識 / positive regulation of neuron projection development / Golgi lumen / positive regulation of protein localization to nucleus / vasodilation / glucose metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / regulation of protein localization / pyridoxal phosphate binding / Platelet degranulation / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / protein-folding chaperone binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / protease binding

ドメイン・相同性:

Serum albumin/Alpha-fetoprotein/Afamin / ALB/AFP/VDB / Serum albumin, N-terminal / Serum albumin, conserved site / Serum albumin-like / Serum albumin family / Albumin domain signature. / Albumin domain profile. / serum albumin / インスリン / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin-like superfamily

構成要素:

インスリン / アルブミン

• 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 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.

登録者

• Line Abildgaard Ryberg (Technical University of Denmark, Lyngby, Denmark)

モデル

• モデル #2465: ; タイプ: atomic / カイ2乗値: 1.115 / P-value: 0.000021; Omokage検索でこの集合体の類似形状データを探す (詳細)
• モデル #2467: ; タイプ: dummy / ダミー原子の半径: 4.20 A / カイ2乗値: 0.887 / P-value: 0.000107; 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 detemir 2:12 complex, P2 symmetry / 試料濃度: 15.6 mg/ml / Entity id: 1320 / 1321
• バッファ: 名称: 8.8 mM Na2HPO4, 10.6 mM m-cresol, 12.2 mM phenol, 140.9 mM glycerol, 56.9 mM NaCl; pH: 7.4

要素 #1320

タイプ: protein / 記述: Human Albumin (Recombumin(R) Alpha, 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 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 #1321

タイプ: protein / 記述: Insulin detemir (Levemir(R), Novo Nordisk A/S) / 分子量: 5.9 / 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: MAX IV I911-4 / 地域: Lund / 国: Sweden / 線源: X-ray synchrotronシンクロトロン / 波長: 0.091 Å / スペクトロメータ・検出器間距離: 1.962 mm
• 検出器: 名称: Pilatus 1M / タイプ: Dectris / Pixsize x: 172 mm

スキャン

タイトル: Albumin-insulin detemir 2:12 complex, P2 symmetry
測定日: 2015年9月25日 / セル温度: 20 °C / 照射時間: 30 sec. / フレーム数: 4 / 単位: 1/nm /

	Min	Max
Q	0.0845	5.4054

距離分布関数 P(R)

ソフトウェア P(R): GNOM 5.0 / ポイント数: 243 /

	Min	Max
Q	0.160547	1.47447
P(R) point	1	243
R	0	19.5

結果

D max: 19.5 / カーブのタイプ: single_conc /

	実験値	Porod
分子量	208.3 kDa	206.3 kDa
体積	-	309.45 nm3

	P(R)	Guinier
前方散乱 I0	0.1522	0.15
慣性半径, Rg	5.694 nm	5.41 nm