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- PDB-6eds: Structure of Cysteine-free Human Insulin-Degrading Enzyme in comp... -

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Basic information

Entry
Database: PDB / ID: 6eds
TitleStructure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Glucagon and Substrate-selective Macrocyclic Inhibitor 63
Components
  • Glucagon
  • Insulin-degrading enzyme
KeywordsHYDROLASE/INHIBITOR / Insulin / Glucagon / Diabetes / Exo-site / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


glucagon receptor binding / insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / protein kinase A signaling / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / negative regulation of execution phase of apoptosis ...glucagon receptor binding / insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / protein kinase A signaling / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / negative regulation of execution phase of apoptosis / feeding behavior / insulin binding / regulation of aerobic respiration / peptide catabolic process / positive regulation of calcium ion import / amyloid-beta clearance / peroxisomal matrix / positive regulation of insulin secretion involved in cellular response to glucose stimulus / Synthesis, secretion, and deacylation of Ghrelin / amyloid-beta metabolic process / Insulin receptor recycling / positive regulation of gluconeogenesis / regulation of insulin secretion / cellular response to glucagon stimulus / peptide binding / proteolysis involved in protein catabolic process / response to activity / gluconeogenesis / Peroxisomal protein import / protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / hormone activity / metalloendopeptidase activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / positive regulation of protein catabolic process / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / positive regulation of protein binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / peroxisome / insulin receptor signaling pathway / glucose homeostasis / virus receptor activity / basolateral plasma membrane / secretory granule lumen / G alpha (s) signalling events / endopeptidase activity / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / Ub-specific processing proteases / G protein-coupled receptor signaling pathway / receptor ligand activity / endoplasmic reticulum lumen / external side of plasma membrane / signaling receptor binding / negative regulation of apoptotic process / cell surface / protein homodimerization activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / extracellular region / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Glucagon / Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones ...Glucagon / Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / Cytochrome Bc1 Complex; Chain A, domain 1 / Metalloenzyme, LuxS/M16 peptidase-like / Peptidase M16, zinc-binding site / Insulinase family, zinc-binding region signature. / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
1,4-DIETHYLENE DIOXIDE / Chem-J22 / DI(HYDROXYETHYL)ETHER / Pro-glucagon / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.18071730876 Å
AuthorsTan, G.A. / Seeliger, M.A. / Maianti, J.P. / Liu, D.R. / Welsh, A.J.
Citation
Journal: Nat.Chem.Biol. / Year: 2019
Title: Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme.
Authors: Maianti, J.P. / Tan, G.A. / Vetere, A. / Welsh, A.J. / Wagner, B.K. / Seeliger, M.A. / Liu, D.R.
#1: Journal: Nature / Year: 2014
Title: Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.
Authors: Maianti, J.P. / McFedries, A. / Foda, Z.H. / Kleiner, R.E. / Du, X.Q. / Leissring, M.A. / Tang, W.J. / Charron, M.J. / Seeliger, M.A. / Saghatelian, A. / Liu, D.R.
History
DepositionAug 10, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support
Revision 1.2May 29, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / software / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin-degrading enzyme
B: Insulin-degrading enzyme
C: Glucagon
D: Glucagon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)235,21012
Polymers233,3564
Non-polymers1,8548
Water00
1
A: Insulin-degrading enzyme
C: Glucagon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,6056
Polymers116,6782
Non-polymers9274
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2870 Å2
ΔGint-1 kcal/mol
Surface area37500 Å2
MethodPISA
2
B: Insulin-degrading enzyme
D: Glucagon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)117,6056
Polymers116,6782
Non-polymers9274
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2770 Å2
ΔGint-1 kcal/mol
Surface area37470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)263.119, 263.119, 90.322
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number170
Space group name H-MP65
Space group name HallP65
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: -x,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
12
22

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111ASNASNPROPROchain 'A'AA43 - 9672 - 926
121ILEILEHISHISchain 'A'AA978 - 1011937 - 970
211ASNASNPROPRO(chain 'B' and (resid 43 through 526 or (resid 527...BB43 - 9672 - 926
221ILEILEHISHIS(chain 'B' and (resid 43 through 526 or (resid 527...BB978 - 1011937 - 970
112HISHISTHRTHRchain 'C'CC1 - 51 - 5
122PHEPHEASNASNchain 'C'CC22 - 2822 - 28
212HISHISTHRTHRchain 'D'DD1 - 51 - 5
222PHEPHEASNASNchain 'D'DD22 - 2822 - 28

NCS ensembles :
ID
1
2

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Components

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Protein / Protein/peptide , 2 types, 4 molecules ABCD

#1: Protein Insulin-degrading enzyme / Abeta-degrading protease / Insulin protease / Insulinase / Insulysin


Mass: 113191.031 Da / Num. of mol.: 2
Mutation: C110L, E111Q, C171S, C178A, C257V, C414L, C573N, C590S, C789S, C812A, C819A, C904S, C966N, C974A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P14735, insulysin
#2: Protein/peptide Glucagon


Mass: 3486.781 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Glucagon, marketed as Glucagen and manufactured by Boehringer Ingelheim.
Source: (gene. exp.) Homo sapiens (human) / Gene: GCG / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01275

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Non-polymers , 4 types, 8 molecules

#3: Chemical ChemComp-J22 / {(8R,9S,10S)-9-(2',3'-dimethyl[1,1'-biphenyl]-4-yl)-6-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]decan-10-yl}methanol


Mass: 494.649 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H34N4O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EPE / 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID / HEPES


Mass: 238.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18N2O4S / Comment: pH buffer*YM
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical ChemComp-DIO / 1,4-DIETHYLENE DIOXIDE


Mass: 88.105 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H8O2

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.01 Å3/Da / Density % sol: 69.32 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES pH 7.0, 12% Tacsimate pH 7.0, 13% PEGMME, 10% Dioxane
PH range: 6.8-7.0 / Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.979341 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979341 Å / Relative weight: 1
ReflectionResolution: 3.18→131.559 Å / Num. obs: 60302 / % possible obs: 100 % / Redundancy: 20.9 % / Biso Wilson estimate: 57.9001204686 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.369 / Rpim(I) all: 0.083 / Rrim(I) all: 0.378 / Net I/σ(I): 10.98
Reflection shellResolution: 3.181→3.2356 Å

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Cootmodel building
XDSdata reduction
autoPROCdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4LTE

4lte


Resolution: 3.18071730876→131.559 Å / SU ML: 0.332870484009 / Cross valid method: FREE R-VALUE / σ(F): 1.33583552402 / Phase error: 21.3338903277
RfactorNum. reflection% reflectionSelection details
Rfree0.222083555612 2869 4.76127254925 %R-free arrays for test set were copied from a different, previously refined crystal structure of ligand-bound IDE (different crystal, but identical protein and ligands). Additionally, Rfree array for test set was further expanded to resolution range of crystal.
Rwork0.176784619198 ---
obs0.178934820394 60257 99.9270327192 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 51.5855318537 Å2
Refinement stepCycle: LAST / Resolution: 3.18071730876→131.559 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15800 0 126 0 15926
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038273187095116328
X-RAY DIFFRACTIONf_angle_d0.64529426052722100
X-RAY DIFFRACTIONf_chiral_restr0.04169539744712366
X-RAY DIFFRACTIONf_plane_restr0.004168016388652850
X-RAY DIFFRACTIONf_dihedral_angle_d14.2339699189832
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1807-3.23560.2681352334061400.2400794743112867X-RAY DIFFRACTION100
3.2356-3.29440.3164305129721410.2509292804792847X-RAY DIFFRACTION100
3.2944-3.35780.3068260466871430.2448124058512852X-RAY DIFFRACTION100
3.3578-3.42630.2853433289871420.2420508851022840X-RAY DIFFRACTION100
3.4263-3.50080.2758486812551420.2234058463382849X-RAY DIFFRACTION100
3.5008-3.58230.2687991582421420.2115791720392843X-RAY DIFFRACTION100
3.5823-3.67190.2299944564121360.1992003545562852X-RAY DIFFRACTION100
3.6719-3.77110.275470737141470.1992616811522892X-RAY DIFFRACTION100
3.7711-3.88210.2559373813611380.1957820712252813X-RAY DIFFRACTION100
3.8821-4.00740.274620198141430.1925867193312862X-RAY DIFFRACTION100
4.0074-4.15070.2334799267341510.1780633337642892X-RAY DIFFRACTION100
4.1507-4.31690.21102222531400.1513588369972858X-RAY DIFFRACTION100
4.3169-4.51330.152458154931450.1365064268642855X-RAY DIFFRACTION100
4.5133-4.75130.155244994851490.1288111677952876X-RAY DIFFRACTION100
4.7513-5.0490.170788005241430.1357232224872869X-RAY DIFFRACTION100
5.049-5.43880.2208910947031450.1524880784532862X-RAY DIFFRACTION99.9667553191
5.4388-5.98620.2127354937971430.174522980122898X-RAY DIFFRACTION100
5.9862-6.85240.2185050593181440.1769404223292887X-RAY DIFFRACTION100
6.8524-8.6330.2001845327471470.1529569750932920X-RAY DIFFRACTION100
8.633-131.67210.1781468310071480.1594714605562954X-RAY DIFFRACTION98.6327503975
Refinement TLS params.Method: refined / Origin x: 72.4902556943 Å / Origin y: -78.3115153621 Å / Origin z: 4.86863644608 Å
111213212223313233
T0.219624829456 Å2-0.0509939685964 Å2-0.0109079168917 Å2-0.199521258058 Å2-0.0624559920884 Å2--0.193571918022 Å2
L0.258352041512 °20.138994572921 °2-0.133036257465 °2-0.0635031657893 °2-0.106644472432 °2--0.0493262852621 °2
S0.0308750590584 Å °0.027254757198 Å °0.000221417665649 Å °0.017716643231 Å °-0.0291341282511 Å °-0.00259016592314 Å °0.00653728216513 Å °-0.0306840269724 Å °0.00117384039258 Å °
Refinement TLS groupSelection details: all

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