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- PDB-4z76: Weak TCR binding to an unstable insulin epitope drives type 1 diabetes -

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Basic information

Entry
Database: PDB / ID: 4z76
TitleWeak TCR binding to an unstable insulin epitope drives type 1 diabetes
Components
  • Beta-2-microglobulin
  • H-2 class I histocompatibility antigen, K-D alpha chain
  • Insulin
KeywordsIMMUNE SYSTEM / Immunoglobulin / H-2Kd / Type 1 Diabetes
Function / homology
Function and homology information


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 / antigen processing and presentation of exogenous peptide antigen via MHC class I ...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 / antigen processing and presentation of exogenous peptide antigen via MHC class I / positive regulation of respiratory burst / negative regulation of acute inflammatory response / MHC class I protein binding / Regulation of gene expression in beta cells / inner ear development / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / 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 / activation of protein kinase B activity / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / positive regulation of insulin receptor signaling pathway / Signal attenuation / fatty acid homeostasis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / regulation of protein localization to plasma membrane / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / 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 / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / negative regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / positive regulation of glycolytic process / positive regulation of cytokine production / endosome lumen / positive regulation of long-term synaptic potentiation / transferrin transport / acute-phase response / cellular response to iron ion / lumenal side of endoplasmic reticulum membrane / positive regulation of D-glucose import / positive regulation of protein secretion / Endosomal/Vacuolar pathway / insulin receptor binding / positive regulation of cell differentiation / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / Regulation of insulin secretion / peptide antigen assembly with MHC class II protein complex / cellular response to iron(III) ion / wound healing / MHC class II protein complex / negative regulation of forebrain neuron differentiation / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / HFE-transferrin receptor complex / MHC class I peptide loading complex / response to molecule of bacterial origin / hormone activity / positive regulation of neuron projection development / T cell mediated cytotoxicity / positive regulation of T cell cytokine production / antigen processing and presentation of endogenous peptide antigen via MHC class I / negative regulation of protein catabolic process / antigen processing and presentation of exogenous peptide antigen via MHC class II / regulation of synaptic plasticity / positive regulation of immune response / MHC class I protein complex / positive regulation of T cell activation / peptide antigen binding / positive regulation of receptor-mediated endocytosis / negative regulation of neurogenesis / cellular response to nicotine / positive regulation of T cell mediated cytotoxicity / multicellular organismal-level iron ion homeostasis / Golgi lumen / positive regulation of protein localization to nucleus / cognition / vasodilation / Modulation by Mtb of host immune system / specific granule lumen
Similarity search - Function
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 / MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 ...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 / MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Immunoglobulin-like / Sandwich / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Insulin / H-2 class I histocompatibility antigen, K-D alpha chain / Beta-2-microglobulin
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.88 Å
Model detailsG9V in H-2Kd, Triclinic Form
AuthorsRizkallah, P.J. / Cole, D.K.
CitationJournal: J.Biol.Chem. / Year: 2015
Title: Distortion of the Major Histocompatibility Complex Class I Binding Groove to Accommodate an Insulin-derived 10-Mer Peptide.
Authors: Motozono, C. / Pearson, J.A. / De Leenheer, E. / Rizkallah, P.J. / Beck, K. / Trimby, A. / Sewell, A.K. / Wong, F.S. / Cole, D.K.
History
DepositionApr 6, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 24, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Database references
Revision 1.2Aug 12, 2015Group: Database references
Revision 1.3Oct 23, 2024Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: H-2 class I histocompatibility antigen, K-D alpha chain
B: Beta-2-microglobulin
C: Insulin
D: H-2 class I histocompatibility antigen, K-D alpha chain
E: Beta-2-microglobulin
F: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)92,65930
Polymers90,5696
Non-polymers2,09024
Water8,377465
1
A: H-2 class I histocompatibility antigen, K-D alpha chain
B: Beta-2-microglobulin
C: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,16314
Polymers45,2853
Non-polymers87911
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6980 Å2
ΔGint-92 kcal/mol
Surface area18830 Å2
MethodPISA
2
D: H-2 class I histocompatibility antigen, K-D alpha chain
E: Beta-2-microglobulin
F: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,49516
Polymers45,2853
Non-polymers1,21113
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6640 Å2
ΔGint-161 kcal/mol
Surface area19190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)47.990, 62.370, 72.310
Angle α, β, γ (deg.)69.810, 85.760, 87.050
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
12B
22E

NCS domain segments:

Component-ID: _ / Beg auth comp-ID: MET / Beg label comp-ID: MET / Refine code: _

Dom-IDEns-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROAA0 - 2761 - 277
21PROPRODD0 - 2761 - 277
12METMETBB0 - 991 - 100
22METMETEE0 - 991 - 100

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ADBE

#1: Protein H-2 class I histocompatibility antigen, K-D alpha chain / Leukocyte antigen heavy chain / H-2K(D)


Mass: 32353.016 Da / Num. of mol.: 2 / Fragment: UNP residues 22-296
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: H2-K1, H2-K / Plasmid: pGMT7 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): rosetta / References: UniProt: P01902
#2: Protein Beta-2-microglobulin


Mass: 11879.356 Da / Num. of mol.: 2 / Fragment: UNP residues 21-119
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Plasmid: pGMT7 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): rosetta / References: UniProt: P61769

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Protein/peptide , 1 types, 2 molecules CF

#3: Protein/peptide Insulin


Mass: 1052.269 Da / Num. of mol.: 2 / Fragment: UNP residues 39-47
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: synthetic construct (others) / References: UniProt: P01308

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Non-polymers , 4 types, 489 molecules

#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 465 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.24 Å3/Da / Density % sol: 44.99 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 8
Details: G9V crystals were grown in 20% PEG 6000, 0.2 M calcium chloride, 0.1 M Tris propane pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 1.88→38.268 Å / Num. all: 57349 / Num. obs: 57349 / % possible obs: 89.9 % / Redundancy: 2.1 % / Rpim(I) all: 0.099 / Rrim(I) all: 0.144 / Rsym value: 0.057 / Net I/av σ(I): 10.684 / Net I/σ(I): 8.6 / Num. measured all: 122779
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
1.88-1.932.20.2722.6926342450.6430.272289.9
1.93-1.982.10.2113.4865040320.5050.2112.587.8
1.98-2.042.10.1734.1825938720.4260.173386.3
2.04-2.12.10.1594.6770336520.3570.1593.583.7
2.1-2.172.10.1355.3653231220.2940.1354.274.3
2.17-2.252.10.1037.1798437540.2530.1034.792.2
2.25-2.332.20.0977.6806337420.2170.0975.494.7
2.33-2.432.20.0829.2770435710.1870.0826.194.7
2.43-2.542.10.0789.2740734460.1740.0786.594.6
2.54-2.662.10.06711.1699532590.1380.0677.894.1
2.66-2.82.20.05513.1675130980.1190.0559.193.8
2.8-2.972.10.04616.1619829190.1030.04610.593.2
2.97-3.182.10.0417.9567026720.080.0412.591.7
3.18-3.432.10.03718518624600.0670.03714.690
3.43-3.762.10.03320.3462021710.0550.03317.686.9
3.76-4.22.10.02722.1356916940.0480.02720.374.8
4.2-4.852.20.0319.6431019890.0460.0322.298.6
4.85-5.952.20.02726.1365716770.0480.02722.199.2
5.95-8.412.20.03319.3274412720.0560.0332198.9
8.41-38.2682.20.03318.715147020.0480.03325.697.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
xia2data reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.88→38.268 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.933 / WRfactor Rfree: 0.2169 / WRfactor Rwork: 0.1721 / FOM work R set: 0.8159 / SU B: 9.281 / SU ML: 0.134 / SU R Cruickshank DPI: 0.1906 / SU Rfree: 0.1647 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.191 / ESU R Free: 0.165 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2296 2886 5.1 %RANDOM
Rwork0.184 ---
obs0.1863 54089 89.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 107.86 Å2 / Biso mean: 27.817 Å2 / Biso min: 9.32 Å2
Baniso -1Baniso -2Baniso -3
1--0.2 Å2-0.59 Å20.54 Å2
2--1.73 Å20.15 Å2
3----1.12 Å2
Refinement stepCycle: final / Resolution: 1.88→38.268 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6394 0 117 465 6976
Biso mean--56.52 33.87 -
Num. residues----772
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0196758
X-RAY DIFFRACTIONr_bond_other_d0.0050.026090
X-RAY DIFFRACTIONr_angle_refined_deg1.7731.9469180
X-RAY DIFFRACTIONr_angle_other_deg1.187313983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7325781
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.97623360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.252151081
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.3361563
X-RAY DIFFRACTIONr_chiral_restr0.1110.2938
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0217612
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021699
X-RAY DIFFRACTIONr_mcbond_it1.2211.3883121
X-RAY DIFFRACTIONr_mcbond_other1.2211.3883120
X-RAY DIFFRACTIONr_mcangle_it2.0382.0713903
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A154210.13
12D154210.13
21B56500.11
22E56500.11
LS refinement shellResolution: 1.88→1.929 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 187 -
Rwork0.28 3808 -
all-3995 -
obs--84.8 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3570.11630.88710.93540.24072.5605-0.04670.0050.22140.00420.0193-0.0261-0.24840.09790.02740.0333-0.02560.01320.0403-0.0350.109548.6953.356336.2979
22.35580.7827-0.9353.6845-1.97732.7534-0.1155-0.1505-0.3652-0.1262-0.0019-0.20290.46990.1330.11740.10770.03330.01030.0758-0.0240.103253.208824.412960.0116
31.71740.0494-0.19440.859-0.20953.7002-0.0185-0.09880.0350.10470.11030.1132-0.0544-0.1426-0.09180.01340.01490.01550.0587-0.03160.080536.365240.36757.1293
41.323-0.3509-0.67681.03860.33143.0552-0.02370.0551-0.1538-0.00370.02450.02080.29310.1013-0.00080.03030.0115-0.00490.0319-0.04870.085224.800820.374632.0997
52.6444-0.08760.57392.496-1.28432.4102-0.05370.19970.41710.004-0.03410.0301-0.47120.0310.08780.12930.0023-0.01340.078-0.02940.125428.887148.86238.3519
61.072-0.22250.17591.2251-0.84544.71110.02450.07480.0037-0.22710.05250.2311-0.0103-0.2819-0.07690.0552-0.017-0.02610.0651-0.04510.117812.358233.051911.2219
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A0 - 180
2X-RAY DIFFRACTION1C1 - 9
3X-RAY DIFFRACTION2A181 - 276
4X-RAY DIFFRACTION3B0 - 99
5X-RAY DIFFRACTION4D0 - 180
6X-RAY DIFFRACTION4F1 - 9
7X-RAY DIFFRACTION5D181 - 276
8X-RAY DIFFRACTION6E0 - 99

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