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

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Basic information

Entry
Database: PDB / ID: 4wdi
TitleWeak TCR binding to an unstable insulin epitope drives type 1 diabetes
Components
  • Beta-2-microglobulinBeta-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 NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / nitric oxide-cGMP-mediated signaling / IRS activation / Insulin processing / regulation of protein secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / nitric oxide-cGMP-mediated signaling / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / antigen processing and presentation of exogenous peptide antigen via MHC class I / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / inner ear development / alpha-beta T cell activation / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / positive regulation of nitric oxide mediated signal transduction / fatty acid homeostasis / regulation of protein localization to plasma membrane / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / beta-2-microglobulin binding / negative regulation of gluconeogenesis / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic 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 receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / activation of protein kinase B activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / Regulation of insulin secretion / acute-phase response / endosome lumen / positive regulation of protein secretion / positive regulation of glucose import / positive regulation of nitric-oxide synthase activity / lumenal side of endoplasmic reticulum membrane / positive regulation of cell differentiation / negative regulation of proteolysis / Endosomal/Vacuolar pathway / regulation of transmembrane transporter activity / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / wound healing / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / regulation of synaptic plasticity / negative regulation of forebrain neuron differentiation / insulin receptor binding / ER to Golgi transport vesicle membrane / regulation of erythrocyte differentiation / peptide antigen assembly with MHC class I protein complex / response to molecule of bacterial origin / regulation of iron ion transport / MHC class I peptide loading complex / HFE-transferrin receptor complex / negative regulation of protein catabolic process / T cell mediated cytotoxicity / hormone activity / cellular response to iron ion / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / cognition / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / positive regulation of neuron projection development / negative regulation of neurogenesis / peptide antigen assembly with MHC class II protein complex / positive regulation of receptor-mediated endocytosis / Golgi lumen
Similarity search - Function
Insulin / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / 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 / Immunoglobulins / Immunoglobulin-like fold / 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 / molecular replacement / Resolution: 2.313 Å
Model detailsG9G 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
DepositionSep 8, 2014Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 24, 2015Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2015Group: Database references

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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)90,93111
Polymers90,4856
Non-polymers4465
Water2,882160
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)45,5937
Polymers45,2433
Non-polymers3504
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5330 Å2
ΔGint-70 kcal/mol
Surface area18860 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)45,3394
Polymers45,2433
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-41 kcal/mol
Surface area18770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.930, 62.690, 72.670
Angle α, β, γ (deg.)68.110, 85.790, 85.180
Int Tables number1
Space group name H-MP1
DetailsChains A, B and C form one biological entity. / Chains D,E,F form one biological entity.

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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 / H-2K(D)


Mass: 32353.016 Da / Num. of mol.: 2 / Fragment: H-2Kd MHC, 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 (E. coli) / Variant (production host): rosetta / References: UniProt: P01902*PLUS
#2: Protein Beta-2-microglobulin / Beta-2 microglobulin


Mass: 11879.356 Da / Num. of mol.: 2 / Fragment: Human beta2-microglobulin, residues 21-219
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: 1010.190 Da / Num. of mol.: 2
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 , 3 types, 165 molecules

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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 160 / Source method: isolated from a natural source / Formula: H2O

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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: 2.18 Å3/Da / Density % sol: 43.64 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 20% PEG 3350, 0.2 M Sodium malonate, and 0.1 M Bis-Tris Propane, pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.917 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Feb 9, 2012 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.91731
20.9171
ReflectionResolution: 2.313→29.518 Å / Num. all: 30132 / Num. obs: 30132 / % possible obs: 90.2 % / Redundancy: 2.1 % / Rpim(I) all: 0.081 / Rrim(I) all: 0.12 / Rsym value: 0.068 / Net I/av σ(I): 10 / Net I/σ(I): 8.6 / Num. measured all: 64672
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.31-2.372.20.3512.2491622610.430.351291.5
2.37-2.442.20.3272.3473321890.3910.3272.290.9
2.44-2.512.20.2682.8458021130.3330.2682.589.5
2.51-2.592.20.2632.9446720420.3060.2632.989.8
2.59-2.672.10.1914409519200.240.1913.488.2
2.67-2.762.10.1694.6396018710.2130.1693.986.8
2.76-2.872.10.1256.1330815990.1680.1254.877.6
2.87-2.992.10.1077355416780.1360.107684.6
2.99-3.122.20.0968.2392618200.1150.0967.395
3.12-3.272.10.0769.9365917020.0960.076994.8
3.27-3.452.20.05912.4355316440.080.05910.894.8
3.45-3.662.20.0514.6329515260.0640.0513.194.3
3.66-3.912.20.04714.8317514640.0650.04714.793.7
3.91-4.222.10.03715.9279113200.0530.03716.793
4.22-4.632.10.03718.8250111850.0480.03718.791.1
4.63-5.172.10.03220.5223510510.0490.03219.387.2
5.17-5.972.10.03616.517508400.0470.03618.380.3
5.97-7.322.20.03918.119038670.0460.03917.999.5
7.32-10.352.20.0341915016870.0340.0342299.6
10.35-29.5182.20.029247703530.0290.02923.595

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
PDB_EXTRACT3.15data extraction
SCALAdata scaling
PHASERphasing
GDAdata collection
GDAdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.313→29.518 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.895 / WRfactor Rfree: 0.2791 / WRfactor Rwork: 0.2004 / FOM work R set: 0.8015 / SU B: 19.774 / SU ML: 0.235 / SU R Cruickshank DPI: 0.861 / SU Rfree: 0.3211 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.861 / ESU R Free: 0.321 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2834 1527 5.1 %RANDOM
Rwork0.2061 28604 --
obs0.21 30131 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 100.76 Å2 / Biso mean: 32.807 Å2 / Biso min: 11.48 Å2
Baniso -1Baniso -2Baniso -3
1-1.01 Å2-0.54 Å2-0.1 Å2
2--0.25 Å21.46 Å2
3----2.24 Å2
Refinement stepCycle: final / Resolution: 2.313→29.518 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6388 0 24 160 6572
Biso mean--57.81 32.46 -
Num. residues----772
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0216658
X-RAY DIFFRACTIONr_bond_other_d0.0010.024585
X-RAY DIFFRACTIONr_angle_refined_deg1.5981.9389055
X-RAY DIFFRACTIONr_angle_other_deg0.89311016
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.395778
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.71823.204362
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.666151073
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.9931560
X-RAY DIFFRACTIONr_chiral_restr0.0940.2910
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0217494
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021492
X-RAY DIFFRACTIONr_mcbond_it0.61.53886
X-RAY DIFFRACTIONr_mcbond_other0.1351.51560
X-RAY DIFFRACTIONr_mcangle_it1.08626276
X-RAY DIFFRACTIONr_scbond_it1.7532772
X-RAY DIFFRACTIONr_scangle_it2.6374.52779
LS refinement shellResolution: 2.313→2.373 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 115 -
Rwork0.277 2131 -
all-2246 -
obs--100 %
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)
11.68720.55371.52951.47840.00075.4494-0.1798-0.10190.44820.2549-0.0941-0.1711-1.29720.29080.27390.4029-0.0895-0.07180.13160.00620.241548.345653.895135.9216
23.12061.2555-1.58226.9749-3.48372.6819-0.15630.1535-0.3574-0.12950.0645-0.12350.24420.11890.09180.03810.033-0.00130.1028-0.02040.066552.48925.511859.9691
32.2294-0.1679-0.84080.7955-1.51716.353-0.0022-0.0110.06190.20660.02750.179-0.5065-0.4489-0.02540.09040.03530.03150.0683-0.03750.114336.442441.371957.0621
41.3909-0.8398-1.32061.15660.85494.9306-0.0872-0.1003-0.2936-0.0007-0.00050.03750.96710.07120.08770.2895-0.02080.02340.1110.04380.128624.964820.486731.9221
53.471-1.76051.9456.4273-4.02844.3183-0.1216-0.00560.4850.0162-0.041-0.1267-0.32880.10040.16270.0573-0.0173-0.01010.0459-0.00270.071628.919848.84157.8514
62.326-0.1320.20371.3964-2.0857.41630.15250.0053-0.0552-0.2376-0.05070.30090.4213-0.5414-0.10180.0547-0.0095-0.04920.1106-0.04630.109112.878632.87410.825
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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