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- PDB-6nha: Crystal structure of SYNT001, a human FcRn blocking monoclonal an... -

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Basic information

Entry
Database: PDB / ID: 6nha
TitleCrystal structure of SYNT001, a human FcRn blocking monoclonal antibody
Components
  • Beta-2-microglobulinBeta-2 microglobulin
  • IgG receptor FcRn large subunit p51
  • SYNT001-Fab heavy chain
  • SYNT001-Fab light chain
KeywordsIMMUNE SYSTEM / FcRn / B2M / Circulating IgG and IgG immune complex / SYNT001
Function / homology
Function and homology information


IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor / IgG binding / beta-2-microglobulin binding / 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 ...IgG immunoglobulin transcytosis in epithelial cells mediated by FcRn immunoglobulin receptor / IgG binding / beta-2-microglobulin binding / 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 / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / negative regulation of forebrain neuron differentiation / 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 / cellular response to iron ion / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / MHC class I protein complex / multicellular organismal-level iron ion homeostasis / negative regulation of neurogenesis / peptide antigen assembly with MHC class II protein complex / positive regulation of receptor-mediated endocytosis / positive regulation of T cell mediated cytotoxicity / MHC class II protein complex / cellular response to nicotine / recycling endosome membrane / specific granule lumen / phagocytic vesicle membrane / peptide antigen binding / positive regulation of cellular senescence / antigen processing and presentation of exogenous peptide antigen via MHC class II / negative regulation of epithelial cell proliferation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / Interferon gamma signaling / positive regulation of immune response / Modulation by Mtb of host immune system / sensory perception of smell / positive regulation of T cell activation / positive regulation of protein binding / tertiary granule lumen / DAP12 signaling / negative regulation of neuron projection development / MHC class II protein complex binding / late endosome membrane / T cell differentiation in thymus / ER-Phagosome pathway / iron ion transport / early endosome membrane / protein refolding / protein homotetramerization / intracellular iron ion homeostasis / amyloid fibril formation / learning or memory / endosome membrane / immune response / Amyloid fiber formation / lysosomal membrane / external side of plasma membrane / endoplasmic reticulum lumen / Golgi membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / Golgi apparatus / endoplasmic reticulum / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / 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 ...MHC class I-like antigen recognition-like / Murine Class I Major Histocompatibility Complex, H2-DB; Chain A, domain 1 / 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
IgG receptor FcRn large subunit p51 / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.381 Å
AuthorsBlumberg, R.S. / Cheung, J. / Mahmood, A. / Gandhi, A.K.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Sci Adv / Year: 2019
Title: Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.
Authors: Blumberg, L.J. / Humphries, J.E. / Jones, S.D. / Pearce, L.B. / Holgate, R. / Hearn, A. / Cheung, J. / Mahmood, A. / Del Tito, B. / Graydon, J.S. / Stolz, L.E. / Bitonti, A. / Purohit, S. / ...Authors: Blumberg, L.J. / Humphries, J.E. / Jones, S.D. / Pearce, L.B. / Holgate, R. / Hearn, A. / Cheung, J. / Mahmood, A. / Del Tito, B. / Graydon, J.S. / Stolz, L.E. / Bitonti, A. / Purohit, S. / de Graaf, D. / Kacena, K. / Andersen, J.T. / Christianson, G.J. / Roopenian, D.C. / Hubbard, J.J. / Gandhi, A.K. / Lasseter, K. / Pyzik, M. / Blumberg, R.S.
History
DepositionDec 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: IgG receptor FcRn large subunit p51
B: Beta-2-microglobulin
L: SYNT001-Fab light chain
H: SYNT001-Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4047
Polymers89,7824
Non-polymers6223
Water2,990166
1
A: IgG receptor FcRn large subunit p51
B: Beta-2-microglobulin
hetero molecules

L: SYNT001-Fab light chain
H: SYNT001-Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,4047
Polymers89,7824
Non-polymers6223
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation1_565x,y+1,z1
Buried area8510 Å2
ΔGint-20 kcal/mol
Surface area36680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.830, 77.664, 215.605
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein IgG receptor FcRn large subunit p51 / FcRn / IgG Fc fragment receptor transporter alpha chain / Neonatal Fc receptor


Mass: 31072.850 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FCGRT, FCRN / Production host: Homo sapiens (human) / References: UniProt: P55899
#2: Protein Beta-2-microglobulin / Beta-2 microglobulin


Mass: 11748.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Homo sapiens (human) / References: UniProt: P61769

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Antibody , 2 types, 2 molecules LH

#3: Antibody SYNT001-Fab light chain


Mass: 23445.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody SYNT001-Fab heavy chain


Mass: 23515.377 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)

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Non-polymers , 2 types, 169 molecules

#5: Chemical ChemComp-NHE / 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID / N-CYCLOHEXYLTAURINE / CHES / CHES (buffer)


Mass: 207.290 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H17NO3S / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 166 / 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: 3.16 Å3/Da / Density % sol: 61.03 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 9.5 / Details: 0.1M CHES pH 9.5 50% polyethylene glycol 200

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.38→200 Å / Num. obs: 41525 / % possible obs: 92.5 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.107 / Rpim(I) all: 0.044 / Rrim(I) all: 0.116 / Χ2: 1.009 / Net I/σ(I): 7.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.5-2.5461.81616560.4470.7771.9810.53485.5
2.54-2.596.41.43916590.5320.5921.560.55387.1
2.59-2.646.41.22416370.6490.5011.3260.56184.9
2.64-2.696.30.99216820.740.4061.0740.55886.3
2.69-2.756.40.86116450.7970.3520.9320.57685.1
2.75-2.826.30.70216450.8470.2870.760.57785.1
2.82-2.896.40.5516500.9070.2260.5960.60685.9
2.89-2.966.30.42216880.9340.1730.4570.62186.8
2.96-3.056.30.31616920.9660.1310.3430.63688.1
3.05-3.156.30.23617260.9790.0970.2560.67687.9
3.15-3.266.10.18417970.9860.0770.20.78391.9
3.26-3.396.10.14318790.9890.060.1550.85696
3.39-3.556.20.11118990.9930.0470.1210.96798.3
3.55-3.736.30.09519660.9930.040.1031.11999.5
3.73-3.976.60.08719350.9940.0360.0941.29499.6
3.97-4.276.80.07319770.9970.030.0791.509100
4.27-4.7170.06219980.9970.0250.0671.731100
4.71-5.3970.05819950.9970.0240.0631.726100
5.39-6.796.80.05820400.9970.0240.0631.559100
6.79-2006.50.04321530.9990.0180.0461.6399.4

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Processing

Software
NameVersionClassification
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3SQO, 5K59, 4N0F

3sqo

5k59

4n0f


Resolution: 2.381→49.769 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 27.78
RfactorNum. reflection% reflection
Rfree0.2452 2013 4.85 %
Rwork0.1903 --
obs0.193 41519 93.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 142.6 Å2 / Biso mean: 60.3585 Å2 / Biso min: 24.9 Å2
Refinement stepCycle: final / Resolution: 2.381→49.769 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6058 0 39 166 6263
Biso mean--66.94 53.6 -
Num. residues----778
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3812-2.44070.39141010.30962349245078
2.4407-2.50670.34731340.26382588272287
2.5067-2.58050.32691340.24552623275788
2.5805-2.66380.28311500.22472605275588
2.6638-2.7590.29241250.22772621274688
2.759-2.86940.30291220.23412705282790
2.8694-30.30671440.23042754289892
3-3.15810.26021390.22762847298695
3.1581-3.3560.31641390.21872995313499
3.356-3.6150.2641770.209730153192100
3.615-3.97870.2361630.180630073170100
3.9787-4.55410.21941460.151530793225100
4.5541-5.73630.20771540.144730823236100
5.7363-49.780.20071850.181132363421100

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