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Yorodumi- PDB-5wob: Crystal Structure Analysis of Fab1-Bound Human Insulin Degrading ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 5wob | |||||||||
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Title | Crystal Structure Analysis of Fab1-Bound Human Insulin Degrading Enzyme (IDE) in Complex with Insulin | |||||||||
Components |
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Keywords | HYDROLASE / complex | |||||||||
Function / homology | Function and homology information insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / ubiquitin-dependent protein binding / insulin binding / negative regulation of NAD(P)H oxidase activity ...insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / ubiquitin-dependent protein binding / insulin binding / negative regulation of NAD(P)H oxidase activity / regulation of aerobic respiration / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / peptide catabolic process / IRS activation / negative regulation of fatty acid metabolic process / nitric oxide-cGMP-mediated signaling / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / amyloid-beta clearance / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / peroxisomal matrix / positive regulation of respiratory burst / positive regulation of dendritic spine maintenance / alpha-beta T cell activation / negative regulation of acute inflammatory response / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / fatty acid homeostasis / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / regulation of protein localization to plasma membrane / positive regulation of nitric oxide mediated signal transduction / COPI-mediated anterograde transport / negative regulation of lipid catabolic process / amyloid-beta metabolic 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 / transport vesicle / positive regulation of protein autophosphorylation / insulin-like growth factor receptor binding / Insulin receptor recycling / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / positive regulation of glycolytic process / proteolysis involved in protein catabolic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / Regulation of insulin secretion / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / endosome lumen / positive regulation of cytokine production / acute-phase response / regulation of transmembrane transporter activity / positive regulation of protein secretion / positive regulation of cell differentiation / Peroxisomal protein import / peptide binding / positive regulation of glucose import / negative regulation of proteolysis / protein catabolic process / regulation of synaptic plasticity / wound healing / insulin receptor binding / cognition / negative regulation of protein catabolic process / positive regulation of neuron projection development / hormone activity / metalloendopeptidase activity / antigen processing and presentation of endogenous peptide antigen via MHC class I / vasodilation / Golgi lumen / peroxisome / positive regulation of protein localization to nucleus / positive regulation of protein catabolic process / glucose metabolic process / regulation of protein localization / glucose homeostasis / cell-cell signaling / virus receptor activity / insulin receptor signaling pathway / positive regulation of NF-kappaB transcription factor activity / positive regulation of protein binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / basolateral plasma membrane / secretory granule lumen Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) Mus musculoides (Temminck's mouse) | |||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / Resolution: 3.95 Å | |||||||||
Authors | McCord, L.A. / Liang, W.G. / Farcasanu, M. / Wang, A.G. / Koide, S. / Tang, W.J. | |||||||||
Funding support | United States, 1items
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Citation | Journal: Elife / Year: 2018 Title: Ensemble cryoEM elucidates the mechanism of insulin capture and degradation by human insulin degrading enzyme. Authors: Zhening Zhang / Wenguang G Liang / Lucas J Bailey / Yong Zi Tan / Hui Wei / Andrew Wang / Mara Farcasanu / Virgil A Woods / Lauren A McCord / David Lee / Weifeng Shang / Rebecca Deprez- ...Authors: Zhening Zhang / Wenguang G Liang / Lucas J Bailey / Yong Zi Tan / Hui Wei / Andrew Wang / Mara Farcasanu / Virgil A Woods / Lauren A McCord / David Lee / Weifeng Shang / Rebecca Deprez-Poulain / Benoit Deprez / David R Liu / Akiko Koide / Shohei Koide / Anthony A Kossiakoff / Sheng Li / Bridget Carragher / Clinton S Potter / Wei-Jen Tang / Abstract: Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes ...Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type two diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing that IDE displays a large opening between the homologous ~55 kDa N- and C-terminal halves to allow selective substrate capture based on size and charge complementarity. We also used cryoEM, X-ray crystallography, SAXS, and HDX-MS to elucidate the molecular basis of how amyloidogenic peptides stabilize the disordered IDE catalytic cleft, thereby inducing selective degradation by substrate-assisted catalysis. Furthermore, our insulin-bound IDE structures explain how IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds. Together, our studies provide a mechanism for how IDE selectively degrades amyloidogenic peptides and offers structural insights for developing IDE-based therapies. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 5wob.cif.gz | 2.1 MB | Display | PDBx/mmCIF format |
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PDB format | pdb5wob.ent.gz | 1.7 MB | Display | PDB format |
PDBx/mmJSON format | 5wob.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wo/5wob ftp://data.pdbj.org/pub/pdb/validation_reports/wo/5wob | HTTPS FTP |
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-Related structure data
Related structure data | 7041C 7062C 7065C 7066C 7090C 7091C 7092C 7093C 6b3qC 6b70C 6b7yC 6b7zC 6bf6C 6bf7C 6bf8C 6bf9C 6bfcC 4iofS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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Unit cell |
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-Components
#1: Protein | Mass: 114560.578 Da / Num. of mol.: 8 / Fragment: UNP residues 42-1019 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli (E. coli) / References: UniProt: P14735, insulysin #2: Protein/peptide | Mass: 2269.595 Da / Num. of mol.: 8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308 #3: Antibody | Mass: 28201.670 Da / Num. of mol.: 8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Production host: Escherichia coli (E. coli) #4: Antibody | Mass: 25982.098 Da / Num. of mol.: 8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Production host: Escherichia coli (E. coli) #5: Chemical | ChemComp-ZN / |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.28 Å3/Da / Density % sol: 46.08 % |
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Crystal grow | Temperature: 291.15 K / Method: vapor diffusion, hanging drop / pH: 6.5 Details: 0.1M Sodium cacodylate, pH6.5; 0.2M MgCl2; 10% PEG3000, VAPOR DIFFUSION, HANGING DROP, temperature 291.15K |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9792 Å |
Detector | Type: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 11, 2013 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9792 Å / Relative weight: 1 |
Reflection | Resolution: 3.95→50 Å / Num. obs: 108370 / % possible obs: 99.5 % / Observed criterion σ(F): 2.1 / Observed criterion σ(I): 2.1 / Redundancy: 3.3 % / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.13 / Rsym value: 0.12 / Χ2: 1.277 / Net I/σ(I): 7 |
Reflection shell | Resolution: 3.95→4.02 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.672 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 5406 / CC1/2: 0.583 / Rpim(I) all: 0.424 / Rsym value: 0.621 / Χ2: 1.02 / % possible all: 99.8 |
-Processing
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Refinement | Starting model: 4IOF Resolution: 3.95→49.543 Å / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.49
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.95→49.543 Å
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Refine LS restraints |
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LS refinement shell |
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