SASDEV5: Insulin detemir tri-hexamer (Insulin detemir)

基本情報

• 登録情報: データベース: SASBDB / ID: SASDEV5

試料

Insulin detemir tri-hexamer

• Insulin detemir (protein)

機能・相同性

分子機能:

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 / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / positive regulation of protein autophosphorylation / alpha-beta T cell activation / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / Signal attenuation / fatty acid homeostasis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / COPI-mediated anterograde transport / transport vesicle / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / regulation of transmembrane transporter activity / positive regulation of glycolytic process / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / endosome lumen / acute-phase response / positive regulation of D-glucose import / positive regulation of protein secretion / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / wound healing / negative regulation of protein catabolic process / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / cognition / glucose metabolic process / vasodilation / insulin receptor signaling pathway / glucose homeostasis / cell-cell signaling / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protease binding / positive regulation of cell growth / secretory granule lumen / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / 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

ドメイン・相同性:

Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily

構成要素:

Insulin

• 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 #2452: ; タイプ: atomic / 対称性: P1 / カイ2乗値: 1.162; 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 #2453: ; タイプ: dummy / ダミー原子の半径: 2.70 A / 対称性: P1 / カイ2乗値: 0.802 / P-value: 0.000006; 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: Insulin detemir tri-hexamer / 試料濃度: 2.5 mg/ml
• バッファ: 名称: 5.0 mM Na2HPO4, 13.1 mM m-cresol, 15.1 mM phenol, 173.7 mM glycerol, 20.0 mM NaCl; pH: 7.4

要素 #1318

タイプ: protein / 記述: Insulin detemir / 分子量: 5.9 / 分子数: 18 / 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 / 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: Insulin detemir tri-hexamer / 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	5.1828

距離分布関数 P(R)

ソフトウェア P(R): GNOM 5.0 / ポイント数: 428 /

	Min	Max
Q	0.1334	2.45177
P(R) point	1	428
R	0	11.32

結果

D max: 11.32 / カーブのタイプ: single_conc

	実験値	Standard	Porod
分子量	100.3 kDa	100.3 kDa	91.5 kDa
体積	-	-	137.2 nm3

	P(R)	Guinier
前方散乱 I0	0.07362	0.072
慣性半径, Rg	3.35 nm	3.26 nm