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- PDB-6mq3: Structure of Cysteine-free Human Insulin-Degrading Enzyme in comp... -

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Basic information

Entry
Database: PDB / ID: 6mq3
TitleStructure of Cysteine-free Human Insulin-Degrading Enzyme in complex with Substrate-selective Macrocycle Inhibitor 63
ComponentsInsulin-degrading enzyme
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Insulin / Glucagon / Diabetes / Exo-site / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


insulysin / ubiquitin recycling / insulin metabolic process / insulin catabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / insulin binding / regulation of aerobic respiration / peptide catabolic process ...insulysin / ubiquitin recycling / insulin metabolic process / insulin catabolic process / amyloid-beta clearance by cellular catabolic process / hormone catabolic process / bradykinin catabolic process / insulin binding / regulation of aerobic respiration / peptide catabolic process / amyloid-beta clearance / peroxisomal matrix / amyloid-beta metabolic process / Insulin receptor recycling / peptide binding / proteolysis involved in protein catabolic process / Peroxisomal protein import / protein catabolic process / antigen processing and presentation of endogenous peptide antigen via MHC class I / metalloendopeptidase activity / positive regulation of protein catabolic process / insulin receptor signaling pathway / peroxisome / positive regulation of protein binding / virus receptor activity / basolateral plasma membrane / endopeptidase activity / Ub-specific processing proteases / external side of plasma membrane / cell surface / protein homodimerization activity / mitochondrion / proteolysis / extracellular space / extracellular exosome / zinc ion binding / ATP binding / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Peptidase M16, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / 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, middle/third domain / Middle or third domain of peptidase_M16 / : / PQQ synthase PqqF-like, C-terminal lobe domain 4 / : / 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
Chem-J22 / Insulin-degrading enzyme
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.56914708689 Å
AuthorsTan, G.A. / Seeliger, M.A. / Welsh, A.J. / Maianti, J.P. / Liu, D.R.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI) United States
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
DepositionOct 9, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 3, 2019Provider: repository / Type: Initial release
Revision 1.1May 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 1.2Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)227,8486
Polymers226,3822
Non-polymers1,4664
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)263.254, 263.254, 91.234
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

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASNASNPROPROchain 'A'AA43 - 9672 - 926
12ILEILEHISHISchain 'A'AA978 - 1011937 - 970
21ASNASNPROPROchain 'B'BB43 - 9672 - 926
22ILEILEHISHISchain 'B'BB978 - 1011937 - 970

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Components

#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
Details: Cysteine-free catalytically inactive human insulin degrading enzyme
Source: (gene. exp.) Homo sapiens (human) / Gene: IDE / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P14735, insulysin
#2: 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
#3: 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

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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: 4.11 Å3/Da / Density % sol: 70.04 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES pH 6.5, 5% Tacsimate pH 7, 10% 1,4-Dioxane, 14% PEGGMME 5000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.978 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 7, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.978 Å / Relative weight: 1
ReflectionResolution: 3.569→84.704 Å / Num. obs: 43243 / % possible obs: 99.88 % / Redundancy: 4.7 % / Biso Wilson estimate: 75.378971446 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.1076 / Rrim(I) all: 0.1521 / Net I/σ(I): 6.85
Reflection shellResolution: 3.569→3.697 Å / Num. unique obs: 4271 / CC1/2: 0.724 / % possible all: 99.95

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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: 3.56914708689→65.8135 Å / SU ML: 0.265587585081 / Cross valid method: FREE R-VALUE / σ(F): 1.34363886775 / Phase error: 19.4678470776
RfactorNum. reflection% reflection
Rfree0.21090305456 2066 4.77930970667 %
Rwork0.16203545477 --
obs0.164395090488 43228 99.9098620196 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 71.2088458101 Å2
Refinement stepCycle: LAST / Resolution: 3.56914708689→65.8135 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15596 0 100 0 15696
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0018383567649916096
X-RAY DIFFRACTIONf_angle_d0.47608333595621804
X-RAY DIFFRACTIONf_chiral_restr0.03787142197352340
X-RAY DIFFRACTIONf_plane_restr0.003123679848732818
X-RAY DIFFRACTIONf_dihedral_angle_d14.96251045849712
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.5691-3.65220.2847431263211440.2333728763392730X-RAY DIFFRACTION99.9652173913
3.6522-3.74350.2876270635081220.2146838403282691X-RAY DIFFRACTION99.9644633973
3.7435-3.84470.2552729721641390.2065688335452753X-RAY DIFFRACTION100
3.8447-3.95780.2772815476521390.1986185858452738X-RAY DIFFRACTION100
3.9578-4.08550.2666235143341400.1866940702982714X-RAY DIFFRACTION100
4.0855-4.23150.2151590109031370.169164154272717X-RAY DIFFRACTION100
4.2315-4.40090.2209426030951370.1461301001922727X-RAY DIFFRACTION99.965095986
4.4009-4.60120.1715383591641420.1341544594312740X-RAY DIFFRACTION99.9653139091
4.6012-4.84370.1695321175411350.1346096100622747X-RAY DIFFRACTION100
4.8437-5.14710.1708753465791380.1395530426082727X-RAY DIFFRACTION99.9302406697
5.1471-5.54430.220582612591320.1573225612782749X-RAY DIFFRACTION100
5.5443-6.10190.2251250587521470.1711385006972742X-RAY DIFFRACTION99.9308197855
6.1019-6.9840.2135642840131330.1703151656522769X-RAY DIFFRACTION99.8623537509
6.984-8.79570.1528719132461420.1409242886422781X-RAY DIFFRACTION99.9316239316
8.7957-65.82470.186939536741390.1395090700592837X-RAY DIFFRACTION99.2330776926

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