|Entry||Database: SASBDB / ID: SASDEV5|
|Sample||Insulin detemir tri-hexamer|
|Function / homology|
Function and homology information
Signaling by Insulin receptor / negative regulation of glycogen catabolic process / alpha-beta T cell activation / Insulin processing / IRS activation / Insulin receptor recycling / negative regulation of NAD(P)H oxidase activity / nitric oxide-cGMP-mediated signaling pathway / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process ...Signaling by Insulin receptor / negative regulation of glycogen catabolic process / alpha-beta T cell activation / Insulin processing / IRS activation / Insulin receptor recycling / negative regulation of NAD(P)H oxidase activity / nitric oxide-cGMP-mediated signaling pathway / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process / regulation of protein secretion / Regulation of gene expression in beta cells / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of respiratory burst involved in inflammatory response / negative regulation of gluconeogenesis / negative regulation of reactive oxygen species biosynthetic process / positive regulation of cellular protein metabolic process / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / Regulation of insulin secretion / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / regulation of cellular amino acid metabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of nitric oxide mediated signal transduction / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of protein secretion / positive regulation of lipid biosynthetic process / fatty acid homeostasis / endosome lumen / transport vesicle / positive regulation of insulin receptor signaling pathway / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / insulin-like growth factor receptor binding / positive regulation of protein autophosphorylation / positive regulation of glycolytic process / negative regulation of acute inflammatory response / regulation of transmembrane transporter activity / positive regulation of cell differentiation / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / regulation of synaptic plasticity / positive regulation of brown fat cell differentiation / cognition / regulation of protein localization / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / acute-phase response / activation of protein kinase B activity / positive regulation of glucose import / vasodilation / hormone activity / negative regulation of proteolysis / negative regulation of protein catabolic process / insulin receptor binding / positive regulation of protein localization to nucleus / insulin receptor signaling pathway / glucose metabolic process / Golgi lumen / positive regulation of nitric-oxide synthase activity / cell-cell signaling / glucose homeostasis / wound healing / endoplasmic reticulum to Golgi vesicle-mediated transport / positive regulation of MAPK cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of phosphatidylinositol 3-kinase signaling / positive regulation of cell growth / secretory granule lumen / protease binding / positive regulation of NF-kappaB transcription factor activity / positive regulation of cell migration / positive regulation of protein kinase B signaling / Amyloid fiber formation / Golgi membrane / G protein-coupled receptor signaling pathway / amyloid fibril formation / endoplasmic reticulum lumen / regulation of transcription, DNA-templated / positive regulation of gene expression / positive regulation of cell population proliferation / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin-like superfamily / Insulin family signature.
Similarity search - Domain/homology
|Citation||Journal: Acta Crystallogr D Struct Biol / Year: 2019|
Title: Solution structures of long-acting insulin analogues and their complexes with albumin.
Authors: Line A Ryberg / Pernille Sønderby / Fabian Barrientos / Jens T Bukrinski / Günther H J Peters / Pernille Harris /
Abstract: 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.
|Structure viewer||Molecule: |
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Type: atomic / Symmetry: P1 / Chi-square value: 1.162
Search similar-shape structures of this assembly by Omokage search (details)
Type: dummy / Radius of dummy atoms: 2.70 A / Symmetry: P1 / Chi-square value: 0.802 / P-value: 0.000006
Search similar-shape structures of this assembly by Omokage search (details)
|Sample||Name: Insulin detemir tri-hexamer / Specimen concentration: 2.5 mg/ml|
|Buffer||Name: 5.0 mM Na2HPO4, 13.1 mM m-cresol, 15.1 mM phenol, 173.7 mM glycerol, 20.0 mM NaCl|
|Entity #1318||Type: protein / Description: Insulin detemir / Formula weight: 5.9 / Num. of mol.: 18 / References: UniProt: P01308|
GIVEQCCTSI CSLYQLENYC NFVNQHLCGS HLVEALYLVC GERGFFYTPK
|Beam||Instrument name: MAX IV I911-4 / City: Lund / 国: Sweden / Type of source: X-ray synchrotronSynchrotron / Wavelength: 0.091 Å / Dist. spec. to detc.: 1.962 mm|
|Detector||Name: Pilatus 1M / Type: Dectris / Pixsize x: 172 mm|
Title: Insulin detemir tri-hexamer / Measurement date: Sep 25, 2015 / Cell temperature: 20 °C / Exposure time: 30 sec. / Number of frames: 4 / Unit: 1/nm /
|Distance distribution function P(R)|
Sofotware P(R): GNOM 5.0 / Number of points: 428 /
D max: 11.32 / Type of curve: single_conc
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