[English] 日本語
Yorodumi
- PDB-6eds: Structure of Cysteine-free Human Insulin-Degrading Enzyme in comp... -

+
Open data


ID or keywords:

Loading...

-
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 / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / negative regulation of execution phase of apoptosis / feeding behavior ...glucagon receptor binding / insulysin / ubiquitin recycling / insulin catabolic process / insulin metabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / negative regulation of execution phase of apoptosis / feeding behavior / : / ubiquitin-modified protein reader activity / insulin binding / regulation of aerobic respiration / peptide catabolic process / cellular response to glucagon stimulus / amyloid-beta clearance / positive regulation of calcium ion import / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peroxisomal matrix / regulation of insulin secretion / Synthesis, secretion, and deacylation of Ghrelin / amyloid-beta metabolic process / protein kinase A signaling / positive regulation of gluconeogenesis / Insulin receptor recycling / proteolysis involved in protein catabolic process / response to activity / positive regulation of peptidyl-threonine phosphorylation / gluconeogenesis / Peroxisomal protein import / peptide binding / protein catabolic process / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / metalloendopeptidase activity / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / antigen processing and presentation of endogenous peptide antigen via MHC class I / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / peroxisome / positive regulation of protein catabolic process / glucose homeostasis / virus receptor activity / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / positive regulation of protein binding / G alpha (s) signalling events / G alpha (q) signalling events / basolateral plasma membrane / secretory granule lumen / endopeptidase activity / positive regulation of ERK1 and ERK2 cascade / Ub-specific processing proteases / G protein-coupled receptor signaling pathway / 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 / zinc ion binding / extracellular region / 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 / 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 ...Glucagon / Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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
Water0
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

-
Components

-
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

-
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 / 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 / Diethylene glycol


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


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

-
Experimental details

-
Experiment

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

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more