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- PDB-4z77: Weak TCR binding to an unstable insulin epitope drives type 1 diabetes -

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Basic information

Entry
Database: PDB / ID: 4z77
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 / Signaling by Insulin receptor / IRS activation / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / nitric oxide-cGMP-mediated signaling ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic process / Signaling by Insulin receptor / IRS activation / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / nitric oxide-cGMP-mediated signaling / positive regulation of peptide hormone secretion / antigen processing and presentation of exogenous peptide antigen via MHC class I / positive regulation of respiratory burst / 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 / negative regulation of acute inflammatory response / alpha-beta T cell activation / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / negative regulation of protein secretion / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / beta-2-microglobulin binding / fatty acid homeostasis / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / 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 / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / 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 mitotic nuclear division / 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 long-term synaptic potentiation / Regulation of insulin secretion / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / lumenal side of endoplasmic reticulum membrane / positive regulation of nitric-oxide synthase activity / positive regulation of cell differentiation / Endosomal/Vacuolar pathway / regulation of transmembrane transporter activity / positive regulation of glucose import / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / negative regulation of proteolysis / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / regulation of synaptic plasticity / negative regulation of forebrain neuron differentiation / wound healing / 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 / T cell mediated cytotoxicity / hormone activity / negative regulation of protein catabolic process / 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 T cell mediated cytotoxicity / positive regulation of receptor-mediated endocytosis
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: 1.85 Å
Model detailsG9V in H-2Kd, Monoclinic form
AuthorsRizkallah, P.J. / Cole, D.K.
CitationJournal: To Be Published
Title: Weak TCR binding to an unstable insulin epitope drives type 1 diabetes
Authors: Rizkallah, P.J. / Cole, D.K.
History
DepositionApr 6, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 24, 2015Provider: repository / Type: Initial release

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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)97,12534
Polymers90,5696
Non-polymers6,55528
Water7,404411
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)47,80917
Polymers45,2853
Non-polymers2,52514
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7170 Å2
ΔGint-26 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)49,31517
Polymers45,2853
Non-polymers4,03114
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7730 Å2
ΔGint-61 kcal/mol
Surface area18590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.150, 84.530, 72.860
Angle α, β, γ (deg.)90.000, 106.860, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21D
12B
22E

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A0 - 276
2010D0 - 276
1020B0 - 99
2020E0 - 99

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 / 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 , 5 types, 439 molecules

#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-15P / POLYETHYLENE GLYCOL (N=34) / PEG 1500 / Polyethylene glycol


Mass: 1529.829 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C69H140O35 / Comment: precipitant*YM
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#7: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 411 / 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: 2.15 Å3/Da / Density % sol: 42.86 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 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: 1.85→37.099 Å / Num. all: 64020 / Num. obs: 64020 / % possible obs: 97.8 % / Redundancy: 3.7 % / Rpim(I) all: 0.151 / Rrim(I) all: 0.298 / Rsym value: 0.214 / Net I/av σ(I): 2.133 / Net I/σ(I): 11.7 / Num. measured all: 237464
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
1.85-1.93.92.0750.21852247371.4762.0752.298.8
1.9-1.953.91.5610.31801546291.0721.5612.798.6
1.95-2.013.91.2340.41746645320.8531.2343.398.6
2.01-2.073.91.0620.41692243820.7131.062498.5
2.07-2.143.80.8680.51584941870.5710.8684.897.5
2.14-2.213.60.7850.61477340560.5210.7855.398
2.21-2.293.40.6570.71319039160.4610.6576.197.2
2.29-2.393.30.6270.71210936810.4290.6276.695.6
2.39-2.493.90.5070.91445736760.3350.507899.3
2.49-2.623.90.4021.11384635490.2760.4029.499.2
2.62-2.763.80.3061.51283433580.2090.30611.399.1
2.76-2.933.80.2381.91190531400.1740.23813.598.6
2.93-3.133.70.1772.51095529740.1320.17716.798.7
3.13-3.383.60.1283.6986927410.0980.12820.497.5
3.38-3.73.40.0835.7855024880.0650.08325.596.5
3.7-4.143.30.0588.6740222310.0440.05830.894.7
4.14-4.7830.04113.5583119170.0340.04135.393.7
4.78-5.8540.03814.2689917450.0270.03838.798.7
5.85-8.2740.04412.5539013530.030.04437.398
8.27-37.0993.70.02423.826807280.0170.02447.594.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 50.43 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å37.1 Å
Translation2.5 Å37.1 Å

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PHASER2.1.4phasing
REFMAC5.8.0073refinement
PDB_EXTRACT3.15data extraction
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→37.099 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.914 / WRfactor Rfree: 0.229 / WRfactor Rwork: 0.182 / FOM work R set: 0.7798 / SU B: 10.488 / SU ML: 0.157 / SU R Cruickshank DPI: 0.1925 / SU Rfree: 0.1699 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.192 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.253 3073 5.1 %RANDOM
Rwork0.206 ---
obs0.2085 57609 92.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 98.25 Å2 / Biso mean: 28.972 Å2 / Biso min: 8.25 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å20.26 Å2
2--0.13 Å20 Å2
3----0.18 Å2
Refinement stepCycle: final / Resolution: 1.85→37.099 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6394 0 150 411 6955
Biso mean--46.17 34.23 -
Num. residues----772
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0196718
X-RAY DIFFRACTIONr_bond_other_d0.0060.026102
X-RAY DIFFRACTIONr_angle_refined_deg1.8561.9479080
X-RAY DIFFRACTIONr_angle_other_deg1.306314018
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9955768
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.3523.109357
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.703151066
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.6411560
X-RAY DIFFRACTIONr_chiral_restr0.1210.2922
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0217504
X-RAY DIFFRACTIONr_gen_planes_other0.0050.021672
X-RAY DIFFRACTIONr_mcbond_it0.7050.8673087
X-RAY DIFFRACTIONr_mcbond_other0.7050.8673086
X-RAY DIFFRACTIONr_mcangle_it1.1931.2943850
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.15 Å / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumber
11A14703
12D14703
21B5343
22E5343
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 171 -
Rwork0.264 3403 -
all-3574 -
obs--74.61 %
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)
13.69810.0002-1.10140.5818-0.16713.5721-0.0043-0.02-0.04260.0839-0.0138-0.0408-0.11760.30110.01810.0658-0.0223-0.04280.2965-0.0080.031640.665553.16016.3058
24.14380.70121.46322.50570.43653.26180.0530.2435-0.3615-0.2060.0580.18480.4233-0.2593-0.1110.1334-0.0126-0.0190.30580.00670.067.369840.2621-3.0535
34.8697-0.2648-0.78351.2314-0.35782.17820.03590.12040.42080.03780.05530.2539-0.2643-0.1062-0.09120.10680.001-0.01110.2131-0.01340.111516.854961.4841-4.268
41.8462-0.24050.43180.79670.24943.74280.0422-0.0039-0.0110.0313-0.03450.09760.1335-0.0855-0.00770.00910-0.00610.3180.01570.0435-3.843244.89730.7396
55.42410.6614-0.91152.0976-0.35521.26570.0417-0.06310.40030.0809-0.0322-0.2433-0.19070.1174-0.00950.04450.0103-0.0250.3327-0.00420.088230.295154.217442.3483
62.9401-1.03551.35022.1633-0.50654.28590.0583-0.0665-0.21210.1097-0.0043-0.24810.45780.046-0.05410.0761-0.0018-0.03340.25410.02390.090720.919134.433835.1556
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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