SASDEW5: Albumin-insulin detemir 1:6 complex, binding in Südlow's Site II

基本情報

• 登録情報: データベース: SASBDB / ID: SASDEW5

試料

Albumin-insulin detemir 1:6 complex, binding in Südlow's Site II

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

機能・相同性

分子機能:

Ciprofloxacin ADME / exogenous protein binding / cellular response to calcium ion starvation / enterobactin binding / Heme biosynthesis / HDL remodeling / negative regulation of mitochondrial depolarization / negative regulation of NAD(P)H oxidase activity / Prednisone ADME / Heme degradation / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / Aspirin ADME / positive regulation of protein autophosphorylation / antioxidant activity / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / regulation of transmembrane transporter activity / 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 / activation of protein kinase B activity / positive regulation of insulin receptor signaling pathway / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / toxic substance binding / negative regulation of lipid catabolic process / Scavenging of heme from plasma / positive regulation of lipid biosynthetic process / regulation of protein localization to plasma membrane / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / Recycling of bile acids and salts / transport vesicle / nitric oxide-cGMP-mediated signaling / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / platelet alpha granule lumen / positive regulation of glycolytic process / cellular response to starvation / positive regulation of cytokine production / fatty acid binding / positive regulation of long-term synaptic potentiation / endosome lumen / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / Post-translational protein phosphorylation / wound healing / negative regulation of protein catabolic process / Cytoprotection by HMOX1 / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / Golgi lumen / positive regulation of protein localization to nucleus / cognition / glucose metabolic process / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / vasodilation / pyridoxal phosphate binding / insulin receptor signaling pathway / glucose homeostasis / Platelet degranulation / cell-cell signaling / 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 / 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

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 / 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 / Albumin

• 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 #2456: ; タイプ: atomic / 対称性: P1 / カイ2乗値: 1.875; 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 #2457: ; タイプ: dummy / ダミー原子の半径: 2.70 A / 対称性: P1 / カイ2乗値: 0.855 / P-value: 0.000022; 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 1:6 complex, binding in Südlow's Site II; 試料濃度: 8.5 mg/ml / Entity id: 1319 / 1320
• バッファ: 名称: 6.9 mM Na2HPO4, 11.9 mM m-cresol, 13.7 mM phenol, 157.3 mM glycerol, 38.5 mM NaCl; pH: 7.4

要素 #1319

タイプ: protein / 記述: Insulin detemir (Levemir(R), Novo Nordisk A/S) / 分子量: 5.9 / 分子数: 6 / 参照: UniProt: P01308
配列:

GIVEQCCTSI CSLYQLENYC NFVNQHLCGS HLVEALYLVC GERGFFYTPK

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

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: Albumin-insulin detemir 1:6 complex, binding in Südlow's Site II
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: 394 /

	Min	Max
Q	0.122541	2.25631
P(R) point	1	394
R	0	13.03

結果

D max: 13.03 / カーブのタイプ: single_conc /

	実験値	Porod
分子量	102.1 kDa	108.2 kDa
体積	-	162.34 nm3

	P(R)	Guinier
前方散乱 I0	0.07479	0.074
慣性半径, Rg	3.637 nm	3.54 nm